Solid state forms of (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamide and uses thereof

ABSTRACT

The present disclosure relates to: a) solid state forms of hydrobromide salts of Compound 1; b) pharmaceutical compositions comprising one or more solid state forms of hydrobromide salts of Compound 1, and, optionally, a pharmaceutically acceptable carrier; c) methods of treating tumors or cancers by administering one or more solid state forms of hydrobromide salts of Compound 1 to a subject in need thereof; and d) methods for the preparation of solid state forms of Compound 1.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 18/157,592, filed on Jan. 20, 2023, pending, which is adivision of U.S. patent application Ser. No. 17/180,296, filed on Feb.19, 2021, pending, which is a continuation of U.S. patent applicationSer. No. 16/886,622, filed on May 28, 2020, now U.S. Pat. No.10,941,118, which is a division of U.S. patent application Ser. No.16/818,863, filed on Mar. 13, 2020, now U.S. Pat. No. 10,710,966, whichis a division of Ser. No. 16/537,394, filed on Aug. 9, 2019, now U.S.Pat. No. 10,590,087, which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present disclosure relates to: a) solid state forms of hydrobromidesalts of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide (“Compound 1”); b)pharmaceutical compositions comprising one or more solid state forms ofhydrobromide salts of Compound 1, and, optionally, a pharmaceuticallyacceptable carrier; c) methods of treating tumors or cancers byadministering one or more solid state forms of hydrobromide salts ofCompound 1 to a subject in need thereof; and d) methods for thepreparation of solid state forms of hydrobromide salts of Compound 1.

BACKGROUND

(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide (“Compound 1”) is agamma-secretase inhibitor which can inhibit AP-peptide production.

Not all compounds that are gamma-secretase inhibitors havecharacteristics affording the best potential to become usefultherapeutics. Some of these characteristics include high affinity at thegamma-secretase, duration of gamma-secretase deactivation, oralbioavailability, tissue distribution, and stability (e.g., ability toformulate or crystallize, shelf life). Favorable characteristics canlead to improved safety, tolerability, efficacy, therapeutic index,patient compliance, cost efficiency, manufacturing ease, etc.

In addition, the isolation and commercial-scale preparation of a solidstate form of hydrobromide salts of Compound 1 and correspondingpharmaceutical formulations having acceptable solid state properties(including chemical stability, thermal stability, solubility,hygroscopicity, and/or particle size), compound manufacturability(including yield, impurity rejection during crystallization, filtrationproperties, drying properties, and milling properties), and formulationfeasibility (including stability with respect to pressure or compressionforces during tableting) present a number of challenges.

Accordingly, there is a current need for one or more solid state formsof hydrobromide salts of Compound 1 that have an acceptable balance ofthese properties and can be used in the preparation of pharmaceuticallyacceptable solid dosage forms.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure relates to a solid form of ahydrobromide salt of Compound 1. In one embodiment, the solid form is acrystalline form of a hydrobromide salt of Compound 1. In oneembodiment, the solid form is a crystalline form of a dihydrobromidesalt of Compound 1. In another embodiment, the solid form is anamorphous form of the dihydrobromide salt of Compound 1.

In one aspect, the present disclosure relates to a crystalline form of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I)

selected from the group consisting of:

-   -   a) crystalline Form A, wherein Form A is characterized by an        XRPD pattern having peaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2        degrees two theta;    -   b) crystalline Form B, wherein Form B is characterized by an        XRPD pattern substantially as shown in FIG. 4 ;    -   c) crystalline Form D, wherein Form D is characterized by an        XRPD pattern substantially as shown in FIG. 11 ;    -   d) crystalline Form E, wherein Form E is characterized by an        XRPD pattern substantially as shown in FIG. 14 ;    -   e) crystalline Form F, wherein Form F is characterized by an        XRPD pattern substantially as shown in FIG. 17 ;    -   f) crystalline Form F′, wherein Form F′ is characterized by an        XRPD pattern substantially as shown in FIG. 18 ;    -   g) crystalline Form G, wherein Form G is characterized by an        XRPD pattern substantially as shown in FIG. 21 ;    -   h) crystalline Form H, wherein Form H is characterized by an        XRPD pattern substantially as shown in FIG. 22 ;    -   i) crystalline Form H′, wherein Form H′ is characterized by an        XRPD pattern substantially as shown in FIG. 23 ;    -   j) crystalline Form J, wherein Form J is characterized by an        XRPD pattern substantially as shown in FIG. 24 ;    -   k) crystalline Form K, wherein Form K is characterized by an        XRPD pattern substantially as shown in FIG. 25 ;    -   l) crystalline Form L, wherein Form L is characterized by an        XRPD pattern substantially as shown in FIG. 26 ;    -   m) crystalline Form M, wherein Form M is characterized by an        XRPD pattern substantially as shown in FIG. 29 ; and    -   n) crystalline Form N, wherein Form N is characterized by an        XRPD pattern substantially as shown in FIG. 30 .

In one aspect, the present disclosure relates to crystalline Form A of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, crystalline Form A is anhydrous.

In another embodiment, the melting point of crystalline Form A is about254° C.

In another embodiment, Form A is characterized by an XRPD pattern havingpeaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2 degrees two theta. In anotherembodiment, Form A is characterized by an XRPD pattern having peaks at8.8±0.2, 9.8±0.2, 23.3±0.2, 25.4±0.2, 28.0±0.2, and 29.3±0.2 degrees twotheta. In another embodiment, Form A is characterized by an XRPD patternhaving peaks at 8.8±0.2, 9.8±0.2, 20.0±0.2, 23.3±0.2, 25.4±0.2,28.0±0.2, 29.3±0.2, and 32.5±0.2 degrees two theta.

In another embodiment, Form A is characterized by an XRPD patternsubstantially as shown in FIG. 1 . In another embodiment, Form A ischaracterized by a TGA profile substantially as shown in FIG. 2 . Inanother embodiment, Form A is characterized by a DSC profilesubstantially as shown in FIG. 3 .

In another embodiment, Form A has a unit cell that indexes as primitivemonoclinic.

In another embodiment, Form A has a unit cell with an a value of about10.035 Å, a b value of about 7.532 Å, and a c value of about 20.092 Å.In another embodiment, Form A has a unit cell with a volume of about1518.1 Å³.

In another embodiment, Form A is substantially free of other polymorphicforms.

In one embodiment, Form A has a polymorphic purity of at least 90%. Inone embodiment, Form A has a polymorphic purity of at least 99%.

In another embodiment, the Form A has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 μm.

In one aspect, the present disclosure relates to crystalline Form B of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form B is characterized by an XRPD patternsubstantially as shown in FIG. 4 .

In another embodiment, Form B is substantially free of other polymorphicforms.

In another embodiment, Form B has a polymorphic purity of at least 90%.In another embodiment, Form B has a polymorphic purity of at least 99%.

In another embodiment, the Form B has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 μm.

In one aspect, the present disclosure relates to crystalline Form C of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (II),

wherein n is about 1 to 3.

In one embodiment, Form C has one or more characteristics selected fromthe group consisting of a)-d):

-   a) an XRPD pattern substantially as shown in FIG. 5 ;-   b) a TGA profile substantially as shown in FIG. 6 ;-   c) a DSC profile substantially as shown in FIG. 7 ; and-   d) a TG-IR linked spectrum substantially as shown in a figure    selected from a group consisting of FIGS. 8 to 10 .

In another embodiment, Form C has a unit cell that indexes as primitiveorthorhombic.

In another embodiment, Form C has a unit cell with an a value of about7.491 Å, a b value of about 10.353 Å, and a c value of about 48.790 Å.In another embodiment, Form C has a unit cell with a volume of about3783.9 Å³.

In another embodiment, the TGA exhibits that Form C loses at least 8 wt% between about 60° C. and about 190° C. In another embodiment, Form Cexhibits a DSC thermogram that has a first endothermic event at about39° C. and a second endothermic event at about 152° C.

In another embodiment, Form C is substantially free of other polymorphicforms.

In one embodiment, Form C has a polymorphic purity of at least 90%. Inone embodiment, Form C has a polymorphic purity of at least 99%.

In another embodiment, the Form C has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 μm, or a D[4,3] particle size of about5 μm to about 200 μm.

In one aspect, the present disclosure relates to crystalline Form D of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form D has one or more characteristics selected fromthe group consisting of a)-c):

-   a) an XRPD pattern substantially as shown in FIG. 11 ;-   b) a TGA profile substantially as shown in FIG. 12A or FIG. 12B; and-   c) a DSC profile substantially as shown in Line A or Line B of FIG.    13 .

In another embodiment, Form D has a unit cell that indexes as primitivemonoclinic. In another embodiment, Form D has a unit cell with an avalue of about 18.465 Å, a b value of about 7.441 Å, and a c value ofabout 23.885 Å. In another embodiment, Form D has a unit cell with avolume of about 3250.4 Å³.

In another embodiment, the TGA exhibits that Form D loses about 1.2 toabout 2.5 wt % between about 24° C. and about 109° C.

In another embodiment, Form D exhibits a DSC thermogram that has anendothermic event at about 65° C.

In another embodiment, Form D is substantially free of other polymorphicforms.

In one embodiment, Form D has a polymorphic purity of at least 90%. Inone embodiment, Form D has a polymorphic purity of at least 99%.

In another embodiment, the Form D has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 μm.

In one aspect, the present disclosure relates to crystalline Form E of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form E has one or more characteristics selected fromthe group consisting of a)-c):

-   a) an XRPD pattern substantially as shown in FIG. 14 ;-   b) a TGA profile substantially as shown in FIG. 15 ; and-   c) a DSC profile substantially as shown in FIG. 16 .

In another embodiment, the TGA exhibits that Form E loses about 8 wt %between about 28° C. and about 120° C.

In another embodiment, Form E exhibits a DSC thermogram that has anendothermic event at about 80° C.

In another embodiment, Form E is substantially free of other polymorphicforms.

In one embodiment, Form E has a polymorphic purity of at least 90%. Inone embodiment, Form E has a polymorphic purity of at least 99%.

In another embodiment, the Form E has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 μm, or a D[4,3] particle size of about5 μm to about 200 μm.

In one aspect, the present disclosure relates to crystalline Form F of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In another embodiment, Form F is characterized by an XRPD patternsubstantially as shown in FIG. 17 .

In another embodiment, Form F is substantially free of other polymorphicforms.

In one embodiment, Form F has a polymorphic purity of at least 90%. Inone embodiment, Form F has a polymorphic purity of at least 99%.

In another embodiment, the Form F has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 μm, or a D[4,3] particle size of about5 μm to about 200 μm.

In one aspect, the present disclosure relates to crystalline Form F′ ofa hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form F′ has one or more characteristics selected fromthe group consisting of a)-b):

-   a) an XRPD pattern substantially as shown in FIG. 18 ; and-   b) a TGA profile substantially as shown in FIG. 19 ; and-   c) a DSC profile substantially as shown in FIG. 20 .

In another embodiment, the TGA exhibits that Form F′ loses about 12.6 wt% between about 24° C. and about 90° C. and loses about 15.6 wt %between about 97° C. to about 198° C.

In another embodiment, Form F′ is substantially free of otherpolymorphic forms. In one embodiment, Form F′ has a polymorphic purityof at least 90%. In one embodiment, Form F′ has a polymorphic purity ofat least 99%.

In another embodiment, the Form F′ has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 μm, or a D[4,3] particle size of about5 μm to about 200 μm.

In one aspect, the present disclosure relates to crystalline Form G of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form G is characterized by an XRPD patternsubstantially as shown in FIG. 21 .

In another embodiment, Form G is substantially free of other polymorphicforms. In one embodiment, Form G has a polymorphic purity of at least90%. In one embodiment, Form G has a polymorphic purity of at least 99%.

In another embodiment, the Form G has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 μm.

In one aspect, the present disclosure relates to crystalline Form H of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I)

In one embodiment, Form H is characterized by an XRPD patternsubstantially as shown in FIG. 22 .

In another embodiment, Form H is substantially free of other polymorphicforms. In one embodiment, Form H has a polymorphic purity of at least90%. In one embodiment, Form H has a polymorphic purity of at least 99%.

In another embodiment, the Form H has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 μm.

In one aspect, the present disclosure relates to crystalline Form H′ ofa hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I)

In one embodiment, Form H′ is characterized by an XRPD patternsubstantially as shown in FIG. 23 .

In another embodiment, Form H′ is substantially free of otherpolymorphic forms. In one embodiment, Form H′ has a polymorphic purityof at least 90%. In one embodiment, Form H′ has a polymorphic purity ofat least 99%.

In another embodiment, the Form H′ has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 μm.

In one aspect, the present disclosure relates to crystalline Form J of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form J is characterized by an XRPD patternsubstantially as shown in FIG. 24 .

In another embodiment, Form J is substantially free of other polymorphicforms. In one embodiment, Form J has a polymorphic purity of at least90%. In one embodiment, Form J has a polymorphic purity of at least 99%.

In another embodiment, the Form J has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 μm.

In one aspect, the present disclosure relates to crystalline Form K of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form K is characterized by an XRPD patternsubstantially as shown in FIG. 25 .

In another embodiment, Form K is substantially free of other polymorphicforms. In one embodiment, Form K has a polymorphic purity of at least90%. In one embodiment, Form K has a polymorphic purity of at least 99%.

In another embodiment, the Form K has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 μm.

In one aspect, the present disclosure relates to crystalline Form L of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form L has one or more characteristics selected fromthe group consisting of a)-c):

-   a) an XRPD pattern substantially as shown in FIG. 26 ;-   b) a TGA profile substantially as shown in FIG. 27 ; and-   c) a DSC profile substantially as shown in FIG. 28 .

In another embodiment, Form L exhibits a DSC thermogram that has anendothermic event at about 157° C.

In another embodiment, Form L is substantially free of other polymorphicforms. In one embodiment, Form L has a polymorphic purity of at least90%. In one embodiment, Form L has a polymorphic purity of at least 99%.

In another embodiment, the Form L has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 μm.

In one aspect, the present disclosure relates to crystalline Form M of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I),

In one embodiment, Form M is characterized by an XRPD patternsubstantially as shown in FIG. 29 .

In another embodiment, Form M is substantially free of other polymorphicforms. In one embodiment, Form M has a polymorphic purity of at least90%. In one embodiment, Form M has a polymorphic purity of at least 99%.

In another embodiment, the Form M has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 μm, or a D[4,3] particle size of about5 μm to about 200 μm.

In one aspect, the present disclosure relates to crystalline Form N of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form N is characterized by an XRPD patternsubstantially as shown in FIG. 30 .

In another embodiment, Form N is substantially free of other polymorphicforms. In one embodiment, Form N has a polymorphic purity of at least90%. In one embodiment, Form N has a polymorphic purity of at least 99%.

In another embodiment, the Form N has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 μm, or a D[4,3] particle size of about5 μm to about 200 μm.

In one aspect, the present disclosure relates to amorphous form of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I),

In one embodiment, the amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) ischaracterized by an XRPD pattern substantially as shown in FIG. 31 .

In another embodiment, the amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) issubstantially free of polymorphic forms. In one embodiment, theamorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) has apolymorphic purity of at least 90%. In one embodiment, the amorphousform of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) has apolymorphic purity of at least 99%.

In another embodiment, the amorphous form has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 μm.

In one aspect, the present disclosure relates to a compositioncomprising a crystalline or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 or a D[4,3] particle size of about 5 μmto about 200 In one embodiment, the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl(neopentylamino) propan-2-yl)-1H-imidazol-4-yl)pentanamide is amorphousform. In one embodiment, the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide is a crystalline form.

In one embodiment, the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide is a compound of Formula (I)

In another embodiment, the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide is a compound of Formula (II)

In another embodiment, the crystalline form is selected from the groupconsisting of Form A, Form B, Form C, Form D, Form E, Form F, Form F′,Form G, Form H, Form H′, Form J, Form K, Form L, Form M, and Form N. Inanother embodiment, the crystalline form is Form A.

In one aspect, the present disclosure relates to a pharmaceuticalcomposition comprising one or more of forms or compositions discussedabove and a pharmaceutically acceptable carrier. In one embodiment, thepharmaceutical composition comprises crystalline Form A of the compoundof Formula (I). In one embodiment, the pharmaceutical composition is atablet. In one embodiment, the pharmaceutical composition comprisesabout 25 mg to about 400 mg of the hydrobromide salt of (S)(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. In one embodiment, thepharmaceutical composition comprises about 50 mg of the hydrobromidesalt of (S)(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. In one embodiment, thepharmaceutical composition comprises about 100 mg of the hydrobromidesalt of (S)(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. In one embodiment, thepharmaceutical composition comprises about 150 mg of the hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide.

In one aspect, the present disclosure relates to a method of treatingtumors or cancer comprising administering to a subject in need of suchtreatment one or more of Forms A-N or amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide discussed above. In oneembodiment, the method of treating tumors or cancer comprisesadministering to a subject in need of such treatment crystalline Form Aof a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. In one aspect, the presentdisclosure relates to a method of treating tumors or cancer comprisingadministering to a subject in need of such treatment a pharmaceuticalcomposition comprising one or more of Forms A-N or amorphous form of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide discussed above and apharmaceutically acceptable carrier. In one embodiment, the method oftreating tumors or cancer comprises administering to a subject in needof such treatment a pharmaceutical composition comprising crystallineForm A of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide and a pharmaceuticallyacceptable carrier. In one embodiment of the methods, the tumor isdesmoid tumors. In one embodiment of the methods, the cancer is selectedfrom the group consisting of multiple myeloma, a cancer having amutation in a Notch pathway gene, adenoid cystic carcinoma, and T-cellacute lymphoblastic leukemia. In another embodiment of the methods, thecancer is multiple myeloma. In another embodiment, the cancer is onewith a mutation in a Notch pathway gene. In another embodiment, thecancer is adenoid cystic carcinoma. In another embodiment, the cancer isT-cell acute lymphoblastic leukemia. In another embodiment, the subjectis administered about 50 mg to about 500 mg of the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide daily. In another embodiment,the subject is administered about 100 mg to about 400 mg of thehydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide daily. In another embodiment,the subject is administered about 300 mg of the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide daily. In another embodiment,the subject is administered about 200 mg of the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide daily. In another embodiment,the total daily dose is provided as two separate doses. In anotherembodiment, the total daily dose is provided as two separate doses of150 mg. In another embodiment, the total daily dose is provided as twoseparate doses of 100 mg.

In one aspect, the present disclosure relates to a use of one or more ofForms A-N or amorphous forms of the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide discussed above for themanufacture of a medicament for treating tumors or cancer. In oneembodiment, the present disclosure relates to a use of crystalline FormA of the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide for the manufacture of amedicament for treating tumors or cancer. In one embodiment, the presentdisclosure relates to the pharmaceutical composition discussed above fortreating tumors or cancer. In one embodiment, the use is for treatingdesmoid tumors. In one embodiment, the use is for treating cancerselected from the group consisting of multiple myeloma, a cancer havinga mutation in a Notch pathway gene, adenoid cystic carcinoma, and T-cellacute lymphoblastic leukemia.

In one aspect, the present disclosure relates to one or more of FormsA-N or amorphous forms of the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide discussed above for use in amethod for treatment of tumors or cancer. In one embodiment, the presentdisclosure relates to the pharmaceutical composition discussed above foruse in a method for treatment of tumors or cancer. In one embodiment,the use is for treating desmoid tumors. In one embodiment, the use isfor treating cancer selected from the group consisting of multiplemyeloma, a cancer having a mutation in a Notch pathway gene, adenoidcystic carcinoma, and T-cell acute lymphoblastic leukemia.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a powder X-ray diffraction pattern (“XRPD”) corresponding tocrystalline Form A.

FIG. 2 is a thermogravimetric analysis thermogram (“TGA”) correspondingto crystalline Form A.

FIG. 3 is a differential scanning calorimetry thermogram (“DSC”)corresponding to crystalline Form A.

FIG. 4 is an XRPD corresponding to crystalline Form B.

FIG. 5 is an XRPD corresponding to crystalline Form C.

FIG. 6 is a TGA corresponding to crystalline Form C.

FIG. 7 is a DSC corresponding to crystalline Form C.

FIGS. 8-10 are thermogravimetric infrared analyses (“TG-IR”)corresponding to crystalline Form C.

FIG. 11 is an XRPD corresponding to crystalline Form D.

FIG. 12A is a TGA corresponding to crystalline Form D as prepared.

FIG. 12B is a TGA corresponding to crystalline Form D when vacuum driedat 75° C.

FIG. 13 is a DSC corresponding to crystalline Form D. Line A is the DSCof Form D as prepared. Line B is the DSC of Form D when vacuum dried at75° C.

FIG. 14 is an XRPD corresponding to crystalline Form E.

FIG. 15 is a TGA corresponding to crystalline Form E.

FIG. 16 is a DSC corresponding to crystalline Form E.

FIG. 17 is an XRPD corresponding to crystalline Form F.

FIG. 18 is an XRPD corresponding to crystalline Form F′.

FIG. 19 is a TGA corresponding to crystalline Form F′.

FIG. 20 is a DSC corresponding to crystalline Form F′.

FIG. 21 is an XRPD corresponding to crystalline Form G.

FIG. 22 is an XRPD corresponding to crystalline Form H.

FIG. 23 is an XRPD corresponding to crystalline Form H′.

FIG. 24 is an XRPD corresponding to crystalline Form J.

FIG. 25 is an XRPD corresponding to crystalline Form K.

FIG. 26 is an XRPD corresponding to crystalline Form L.

FIG. 27 is a TGA corresponding to crystalline Form L.

FIG. 28 is a DSC corresponding to crystalline Form L.

FIG. 29 is an XRPD corresponding to crystalline Form M.

FIG. 30 is an XRPD corresponding to crystalline Form N.

FIG. 31 is an XRPD corresponding to amorphous Compound 1 of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well-known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

In this specification and the appended claims, the singular forms “a,”“an” and “the” include plural referents unless the context clearlydictates otherwise. The terms “a” (or “an”), as well as the terms “oneor more,” and “at least one” can be used interchangeably herein. Incertain aspects, the term “a” or “an” means “single.” In other aspects,the term “a” or “an” includes “two or more” or “multiple.”

Furthermore, “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. Thus, the term “and/or” as used in a phrase such as“A and/or B” herein is intended to include “A and B,” “A or B,” “A”(alone), and “B” (alone). Likewise, the term “and/or” as used in aphrase such as “A, B, and/or C” is intended to encompass each of thefollowing aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; Aand C; A and B; B and C; A (alone); B (alone); and C (alone).

The term “Compound 1” refers to the single enantiomer(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat,or mouse. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman subject.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The term “therapeutically effective amount” is meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof a disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a cell, tissue, system, animal, or human, which is being sought by aresearcher, veterinarian, medical doctor, or clinician.

The terms “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refer to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. SeeRemington: The Science and Practice of Pharmacy, 21st Edition,Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook ofPharmaceutical Excipients, 5th Edition, Rowe et al., Eds., ThePharmaceutical Press and the American Pharmaceutical Association: 2005;and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds.,Gower Publishing Company: 2007; Pharmaceutical Preformulation andFormulation, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004(incorporated herein by reference).

The terms “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a condition,disorder, or disease. As used herein, “active ingredient” and “activesubstance” may be an optically active isomer of a compound describedherein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

The term “solvate” refers to a compound provided herein or a saltthereof, which further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Where thesolvent is water, the solvate is a hydrate. Where the solvent includesethanol, the compound can be an ethanol solvate.

The term “polymorph” as used herein refers to a crystalline form of acompound or a salt, hydrate, or solvate thereof, in a particular crystalpacking arrangement. All polymorphs have the same elemental composition.The term “crystalline,” as used herein, refers to a solid state formwhich consists of orderly arrangement of structural units. Differentcrystalline forms of the same compound, or a salt, hydrate, or solvatethereof, arise from different packing of the molecules in the solidstate, which results in different crystal symmetries and/or unit cellparameter. Different crystalline forms usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. See, e.g., Remington's Pharmaceutical Sciences, 18^(th)ed., Mack Publishing, Easton Pa., 173 (1990); The United StatesPharmacopeia, 23^(rd) ed, 1843-1844 (1995) (incorporated herein byreference).

Crystalline forms are most commonly characterized by X-ray powderdiffraction (XRPD). An XRPD pattern of reflections (peaks, typicallyexpressed in degrees 2-theta) is commonly considered a fingerprint of aparticular crystalline form. The relative intensities of the XRPD peakscan widely vary depending on, inter alia, the sample preparationtechnique, crystal size distribution, filters, the sample mountingprocedure, and the particular instrument employed. In some instances,new peaks may be observed or existing peaks may disappear, depending onthe type of instrument or the settings. In some instances, anyparticular peak in an XRPD pattern may appear as a singlet, doublet,triplet, quartet, or multiplet, depending on the type of instrument orthe settings, the sensitivity of the instrument, measuring conditions,and/or purity of the crystalline form. In some instances, any particularpeak in an XRPD may appear in a symmetric shape or in an asymmetricshape, e.g., having a shoulder. Moreover, instrument variation and otherfactors can affect the 2-theta values. A skilled artisan understandingthese variations is capable of discriminating or ascertaining thedefining features or characteristics of a particular crystal form usingXRPD, as well as using other known physicochemical techniques.

The term “amorphous” as applied to a compound refers to a state in whichthe material lacks long range order at the molecular level and,depending upon temperature, may exhibit the physical properties of asolid or a liquid. Typically such materials do not give distinctiveX-ray diffraction patterns and, while exhibiting the properties of asolid, are more formally described as a liquid. Upon heating, a changefrom solid to liquid properties occurs which is characterized by achange of state, typically second order (“glass transition”).

The term “anhydrate” as applied to a compound refers to a solid statewherein the compound contains no structural water within the crystallattice.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicant intends each of those words to be sointerpreted in construing this patent, including the claims below.

II. Solid State Forms

The present disclosure relates to solid state forms of the hydrobromidesalt of Compound 1. As with all pharmaceutical compounds andcompositions, the chemical and physical properties of the hydrobromidesalt of Compound 1 are important in its commercial development. Theseproperties include, but are not limited to: (1) packing properties suchas molar volume, bulk density and hygroscopicity, (2) thermodynamicproperties such as melting temperature, vapor pressure and solubility,(3) kinetic properties such as dissolution rate and stability (includingstability at ambient conditions, especially to moisture and understorage conditions), (4) surface properties such as surface area,wettability, interfacial tension and shape, (5) mechanical propertiessuch as hardness, tensile strength, compactibility, handling, flow andblend; and (6) filtration properties. These properties can affect, forexample, the processing and storage of the compound and pharmaceuticalcompositions comprising the compound.

Solid state forms of the hydrobromide salt of Compound 1 that improveupon one or more of these properties relative to other solid state formsof the compound are desirable. Isolating pharmaceutically acceptablesolid state forms of the compound that can be manufactured andformulated on a commercial-scale has been a challenge.

In one aspect, the present disclosure relates to a crystalline form of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I)

selected from the group consisting of:

-   -   a) crystalline Form A, wherein Form A is characterized by an        XRPD pattern having peaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2        degrees two theta;    -   b) crystalline Form B, wherein Form B is characterized by an        XRPD pattern substantially as shown in FIG. 4 ;    -   c) crystalline Form D, wherein Form D is characterized by an        XRPD pattern substantially as shown in FIG. 11 ;    -   d) crystalline Form E, wherein Form E is characterized by an        XRPD pattern substantially as shown in FIG. 14 ;    -   e) crystalline Form F, wherein Form F is characterized by an        XRPD pattern substantially as shown in FIG. 17 ;    -   f) crystalline Form F′, wherein Form F′ is characterized by an        XRPD pattern substantially as shown in FIG. 18 ;    -   g) crystalline Form G, wherein Form G is characterized by an        XRPD pattern substantially as shown in FIG. 21 ;    -   h) crystalline Form H, wherein Form H is characterized by an        XRPD pattern substantially as shown in FIG. 22 ;    -   i) crystalline Form H′, wherein Form H′ is characterized by an        XRPD pattern substantially as shown in FIG. 23 ;    -   j) crystalline Form J, wherein Form J is characterized by an        XRPD pattern substantially as shown in FIG. 24 ;    -   k) crystalline Form K, wherein Form K is characterized by an        XRPD pattern substantially as shown in FIG. 25 ;    -   l) crystalline Form L, wherein Form L is characterized by an        XRPD pattern substantially as shown in FIG. 26 ;    -   m) crystalline Form M, wherein Form M is characterized by an        XRPD pattern substantially as shown in FIG. 29 ; and    -   n) crystalline Form N, wherein Form N is characterized by an        XRPD pattern substantially as shown in FIG. 30 .

The sections below discuss solid state forms that have been identifiedand selected properties of those solid state forms.

A. Crystalline Form A

In one aspect, the present disclosure relates to crystalline Form A of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, crystalline Form A is anhydrous.

In another embodiment, the melting point of crystalline Form A is about254° C.

In another embodiment, Form A is characterized by an XRPD pattern havingpeaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2 degrees two theta when measuredby Cu Kα radiation. In another embodiment, Form A is characterized by anXRPD pattern having peaks at 8.8±0.2, 9.8±0.2, 23.3±0.2, 25.4±0.2,28.0±0.2, and 29.3±0.2 degrees two theta when measured by Cu Kαradiation. In another embodiment, Form A is characterized by an XRPDpattern having peaks at 8.8±0.2, 9.8±0.2, 20.0±0.2, 23.3±0.2, 25.4±0.2,28.0±0.2, 29.3±0.2, and 32.5±0.2 degrees two theta when measured by CuKα radiation.

In another embodiment, Form A is characterized by an XRPD patternsubstantially as shown in FIG. 1 . In another embodiment, Form A ischaracterized by a TGA profile substantially as shown in FIG. 2 . Inanother embodiment, Form A is characterized by a DSC profilesubstantially as shown in FIG. 3 .

In another embodiment, Form A has a unit cell that indexes as primitivemonoclinic.

In another embodiment, Form A has a unit cell with an a value of about10.035 Å, a b value of about 7.532 Å, and a c value of about 20.092 Å.In another embodiment, Form A has a unit cell with a volume of about1518.1 Å³.

The unit cell parameters for Form A are as follows:

Primitive Bravais Type Monoclinic a [Å] 10.035 b [Å] 7.532 c [Å] 20.092α [deg] 90 β [deg] 91.39 γ [deg] 90 Volume [Å³/cell] 1518.1 ChiralContents? Chiral Extinction Symbol P 1 2₁ 1 Space Group(s) P2₁ (4)

In another embodiment, Form A is substantially free of other polymorphicforms. In another embodiment, Form A has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

B. Crystalline Form B

In one aspect, the present disclosure relates to crystalline Form B of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form B is characterized by an XRPD patternsubstantially as shown in FIG. 4 .

In another embodiment, Form B is substantially free of other polymorphicforms. In another embodiment, Form B has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

C. Crystalline Form C

In one aspect, the present disclosure relates to crystalline Form C of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (II),

wherein n is about 1 to 3.

In one embodiment, Form C has one or more characteristics selected fromthe group consisting of a)-d):

-   a) an XRPD pattern substantially as shown in FIG. 5 ;-   b) a TGA profile substantially as shown in FIG. 6 ;-   c) a DSC profile substantially as shown in FIG. 7 ; and-   d) a TG-IR linked spectrum substantially as shown in a figure    selected from a group consisting of FIGS. 8 to 10 .

In another embodiment, Form C has a unit cell that indexes as primitiveorthorhombic.

In another embodiment, Form C has a unit cell with an a value of about7.491 Å, a b value of about 10.353 Å, and a c value of about 48.790 Å.In another embodiment, Form C has a unit cell with a volume of about3783.9 Å³.

The unit cell parameters for Form C are as follows:

Primitive Bravais Type Orthorhombic a [Å] 7.491 b [Å] 10.353 c [Å]48.790 α [deg] 90 β [deg] 90 γ [deg] 90 Volume [Å³/cell] 3783.9 ChiralContents? Chiral Extinction Symbol P 2₁ 2₁ 2₁ Space Group(s) P2₁2₁2₁(19)

In another embodiment, the TGA exhibits that Form C loses at least 8 wt% between about 60° C. and about 190° C. In another embodiment, Form Cexhibits a DSC thermogram that has a first endothermic event at about39° C. and a second endothermic event at about 152° C.

In another embodiment, Form C is substantially free of other polymorphicforms. In another embodiment, Form C has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

D. Crystalline Form D

In one aspect, the present disclosure relates to crystalline Form D of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form D has one or more characteristics selected fromthe group consisting of a)-c):

-   a) an XRPD pattern substantially as shown in FIG. 11 ;-   b) a TGA profile substantially as shown in FIG. 12A or FIG. 12B; and-   c) a DSC profile substantially as shown in Line A or Line B of FIG.    13 .

In another embodiment, Form D has a unit cell that indexes as primitivemonoclinic. In another embodiment, Form D has a unit cell with an avalue of about 18.465 Å, a b value of about 7.441 Å, and a c value ofabout 23.885 Å. In another embodiment, Form D has a unit cell with avolume of about 3250.4 Å³.

The unit cell parameters for Form D are as follows:

Primitive Bravais Type Monoclinic a [Å] 18.465 b [Å] 7.441 c [Å] 23.885α [deg] 90 β [deg] 97.95 γ [deg] 90 Volume [Å³/cell] 3250.4 ChiralContents? Chiral Extinction Symbol P 1 2₁ 1 Space Group(s) P2₁ (4)

In another embodiment, the TGA exhibits that Form D loses about 1.2 toabout 2.5 wt % between about 24° C. and about 109° C.

In another embodiment, Form D exhibits a DSC thermogram that has anendothermic event at about 65° C.

In another embodiment, Form D is substantially free of other polymorphicforms. In another embodiment, Form D has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

E. Crystalline Form E

In one aspect, the present disclosure relates to crystalline Form E of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form E has one or more characteristics selected fromthe group consisting of a)-c):

-   a) an XRPD pattern substantially as shown in FIG. 14 ;-   b) a TGA profile substantially as shown in FIG. 15 ; and-   c) a DSC profile substantially as shown in FIG. 16 .

In another embodiment, the TGA exhibits that Form E loses about 8 wt %between about 28° C. and about 120° C.

In another embodiment, Form E exhibits a DSC thermogram that has anendothermic event at about 80° C.

In another embodiment, Form E is substantially free of other polymorphicforms. In another embodiment, Form E has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

F. Crystalline Form F

In one aspect, the present disclosure relates to crystalline Form F of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In another embodiment, Form F is characterized by an XRPD patternsubstantially as shown in FIG. 17 .

In another embodiment, Form A is substantially free of other polymorphicforms. In another embodiment, Form A has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

G. Crystalline Form F′

In one aspect, the present disclosure relates to crystalline Form F′ ofa hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form F′ has one or more characteristics selected fromthe group consisting of a)-c):

-   a) an XRPD pattern substantially as shown in FIG. 18 ;-   b) a TGA profile substantially as shown in FIG. 19 ; and-   c) a DSC profile substantially as shown in FIG. 20 .

In another embodiment, the TGA exhibits that Form F′ loses about 12.6 wt% between about 24° C. and about 90° C. and loses about 15.6 wt %between about 97° C. to about 198° C.

In another embodiment, Form A is substantially free of other polymorphicforms. In another embodiment, Form A has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

H. Crystalline Form G

In one aspect, the present disclosure relates to crystalline Form G of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form G is characterized by an XRPD patternsubstantially as shown in FIG. 21 .

In another embodiment, Form G is substantially free of other polymorphicforms. In another embodiment, Form G has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

I. Crystalline Form H

In one aspect, the present disclosure relates to crystalline Form H of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I)

In one embodiment, Form H is characterized by an XRPD patternsubstantially as shown in FIG. 22 .

In another embodiment, Form H is substantially free of other polymorphicforms. In another embodiment, Form H has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

J. Crystalline Form H′

In one aspect, the present disclosure relates to crystalline Form H′ ofa hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I)

In one embodiment, Form H′ is characterized by an XRPD patternsubstantially as shown in FIG. 23 .

In another embodiment, Form H′ is substantially free of otherpolymorphic forms. In another embodiment, Form H′ has a polymorphicpurity of at least 80%, at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, or at least 99%.

K. Crystalline Form J

In one aspect, the present disclosure relates to crystalline Form J of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form J is characterized by an XRPD patternsubstantially as shown in FIG. 24 .

In another embodiment, Form J is substantially free of other polymorphicforms. In another embodiment, Form J has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

L. Crystalline Form K

In one aspect, the present disclosure relates to crystalline Form K of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form K is characterized by an XRPD patternsubstantially as shown in FIG. 25 .

In another embodiment, Form K is substantially free of other polymorphicforms. In another embodiment, Form K has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

M. Crystalline Form L

In one aspect, the present disclosure relates to crystalline Form L of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form L has one or more characteristics selected fromthe group consisting of a)-c):

-   a) an XRPD pattern substantially as shown in FIG. 26 ;-   b) a TGA profile substantially as shown in FIG. 27 ; and-   c) a DSC profile substantially as shown in FIG. 28 .

In another embodiment, Form L exhibits a DSC thermogram that has anendothermic event at about 157° C.

In another embodiment, Form L is substantially free of other polymorphicforms. In another embodiment, Form L has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

N. Crystalline Form M

In one aspect, the present disclosure relates to crystalline Form M of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I),

In one embodiment, Form M is characterized by an XRPD patternsubstantially as shown in FIG. 29 .

In another embodiment, Form M is substantially free of other polymorphicforms. In another embodiment, Form M has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

O. Crystalline Form N

In one aspect, the present disclosure relates to crystalline Form N of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having Formula (I),

In one embodiment, Form N is characterized by an XRPD patternsubstantially as shown in FIG. 30 .

In another embodiment, Form N is substantially free of other polymorphicforms. In another embodiment, Form N has a polymorphic purity of atleast 80%, at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, or atleast 99%.

P. Amorphous

In one aspect, the present disclosure relates to amorphous form of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I),

In one embodiment, the amorphous Compound 1 of Formula (I) ischaracterized by an XRPD pattern substantially as shown in FIG. 31 .

In another embodiment, the amorphous Compound 1 of Formula (I) issubstantially free of polymorphic forms. In another embodiment, theamorphous Compound 1 of Formula (I) has a polymorphic purity of at least80%, at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least99%.

III. Particle Size

In another aspect, the present disclosure relates to the crystalline andamorphous forms discussed above has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the crystalline and amorphous forms discussed abovehave a D[V,0.10] particle size between about 0.5 μm and about 15 μm. Inone embodiment, the crystalline and amorphous forms discussed above havea D[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[V,0.10] particle size between about 0.5 μm and about 5 μm.

In one embodiment, the crystalline and amorphous forms discussed abovehave a D[V,0.50] particle size between about 2 μm and about 30 μm. Inone embodiment, the crystalline and amorphous forms discussed above havea D[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[V,0.50] particle size between about 2 μm and about 20 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[V,0.50] particle size between about 2 μm and about 15 μm.

In one embodiment, the crystalline and amorphous forms discussed abovehave a D[V,0.90] particle size between about 8 μm and about 600 μm. Inone embodiment, the crystalline and amorphous forms discussed above havea D[V,0.90] particle size between about 8 μm and about 500 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[V,0.90] particle size between about 8 μm and about 400 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[V,0.90] particle size between about 8 μm and about 300 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[V,0.90] particle size between about 8 μm and about 200 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[V,0.90] particle size between about 8 μm and about 100 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[V,0.90] particle size between about 8 μm and about 75 μm.

In one embodiment, the crystalline and amorphous forms discussed abovehave a D[4,3] particle size between about 5 μm to about 200 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[4,3] particle size between about 5 μm to about 150 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[4,3] particle size between about 5 μm and about 75 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[4,3] particle size between about 5 μm and about 50 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[4,3] particle size between about 10 μm and about 50 μm. In oneembodiment, the crystalline and amorphous forms discussed above have aD[4,3] particle size between about 10 μm and about 30 μm.

In one embodiment, the Form A has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form A has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form A has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form A has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form A has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form A has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form A has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form A has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form A has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form A has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form A has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form A has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form A has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form A has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form A has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form A has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form A has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Ahas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form A has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form A has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form A has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form A has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form A has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form B has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form B has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form B has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form B has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form B has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form B has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form B has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form B has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form B has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form B has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form B has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form B has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form B has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form B has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form B has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form B has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form B has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Bhas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form B has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form B has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form B has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form B has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form B has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form C has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form C has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form C has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form C has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form C has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form C has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form C has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form C has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form C has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form C has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form C has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form C has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form C has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form C has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form C has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form C has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form C has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Chas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form C has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form C has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form C has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form C has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form C has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form D has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form D has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form D has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form D has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form D has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form D has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form D has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form D has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form D has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form D has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form D has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form D has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form D has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form D has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form D has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form D has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form D has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Dhas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form D has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form D has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form D has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form D has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form D has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form E has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form E has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form E has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form E has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form E has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form E has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form E has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form E has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form E has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form E has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form E has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form E has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form E has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form E has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form E has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form E has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form E has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Ehas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form E has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form E has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form E has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form E has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form E has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form F has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form F has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form F has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form F has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form F has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form F has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form F has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form F has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form F has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form F has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form F has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form F has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form F has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form F has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form F has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form F has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form F has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Fhas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form F has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form F has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form F has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form F has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form F has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form F′ has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form F′ has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form F′ has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form F′ has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form F′ has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form F′ has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form F′ has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form F′ has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form F′ has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form F′ has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form F′ has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form F′ has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form F′ has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form F′ has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form F′ has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form F′ has a D[4,3] particle size between about5 μm to about 200 μm. In one embodiment, the Form F′ has a D[4,3]particle size between about 5 μm to about 150 μm. In one embodiment, theForm F′ has a D[4,3] particle size between about 5 μm and about 100 μm.In one embodiment, the Form F′ has a D[4,3] particle size between about5 μm and about 75 μm. In one embodiment, the Form F′ has a D[4,3]particle size between about 5 μm and about 50 μm. In one embodiment, theForm F′ has a D[4,3] particle size between about 5 μm and about 25 μm.In one embodiment, the Form F′ has a D[4,3] particle size between about10 μm and about 50 μm. In one embodiment, the Form F′ has a D[4,3]particle size between about 10 μm and about 30 μm.

In one embodiment, the Form G has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form G has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form G has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form G has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form G has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form G has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form G has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form G has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form G has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form G has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form G has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form G has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form G has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form G has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form G has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form G has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form G has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Ghas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form G has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form G has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form G has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form G has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form G has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form H has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form H has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form H has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form H has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form H has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form H has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form H has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form H has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form H has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form H has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form H has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form H has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form H has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form H has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form H has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form H has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form H has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Hhas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form H has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form H has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form H has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form H has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form H has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form H′ has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form H′ has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form H′ has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form H′ has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form H′ has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form H′ has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form H′ has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form H′ has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form H′ has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form H′ has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form H′ has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form H′ has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form H′ has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form H′ has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form H′ has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form H′ has a D[4,3] particle size between about5 μm to about 200 μm. In one embodiment, the Form H′ has a D[4,3]particle size between about 5 μm to about 150 μm. In one embodiment, theForm H′ has a D[4,3] particle size between about 5 μm and about 100 μm.In one embodiment, the Form H′ has a D[4,3] particle size between about5 μm and about 75 μm. In one embodiment, the Form H′ has a D[4,3]particle size between about 5 μm and about 50 μm. In one embodiment, theForm H′ has a D[4,3] particle size between about 5 μm and about 25 μm.In one embodiment, the Form H′ has a D[4,3] particle size between about10 μm and about 50 μm. In one embodiment, the Form H′ has a D[4,3]particle size between about 10 μm and about 30 μm.

In one embodiment, the Form J has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form J has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form H has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form H has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form J has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form J has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form J has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form J has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form J has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form J has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form J has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form J has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form J has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form J has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form J has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form J has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form J has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Jhas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form J has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form J has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form J has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form J has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form J has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form K has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form K has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form K has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form K has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form K has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form K has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form K has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form K has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form K has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form K has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form K has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form K has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form K has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form K has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form K has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form K has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form K has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Khas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form K has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form K has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form K has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form K has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form K has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form L has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form L has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form L has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form L has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form L has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form L has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form L has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form L has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form L has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form L has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form L has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form L has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form L has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form L has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form L has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form L has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form L has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Lhas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form L has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form L has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form L has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form L has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form L has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the Form M has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form M has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form M has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form M has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form M has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form M has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form M has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form M has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form M has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form M has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form M has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form M has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form M has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form M has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form M has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form M has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form M has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Mhas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form M has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form M has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form M has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form M has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form M has a D[4,3] particlesize between about 10 μm and about 30 μmμm.

In one embodiment, the Form N has one or more of a D[V,0.10] particlesize between about 0.5 μm and about 15 μm, a D[V,0.50] particle sizebetween about 2 μm and about 30 μm, a D[V,0.90] particle size betweenabout 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm toabout 200 μm.

In one embodiment, the Form N has a D[V,0.10] particle size betweenabout 0.5 μm and about 15 μm. In one embodiment, the Form N has aD[V,0.10] particle size between about 0.5 μm and about 10 μm. In oneembodiment, the Form N has a D[V,0.10] particle size between about 0.5μm and about 5 μm.

In one embodiment, the Form N has a D[V,0.50] particle size betweenabout 2 μm and about 30 μm. In one embodiment, the Form N has aD[V,0.50] particle size between about 2 μm and about 25 μm. In oneembodiment, the Form N has a D[V,0.50] particle size between about 2 μmand about 20 μm. In one embodiment, the Form N has a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the Form N has a D[V,0.90] particle size betweenabout 8 μm and about 600 μm. In one embodiment, Form N has a D[V,0.90]particle size between about 8 μm and about 500 μm. In one embodiment,Form N has a D[V,0.90] particle size between about 8 μm and about 400μm. In one embodiment, Form N has a D[V,0.90] particle size betweenabout 8 μm and about 300 μm. In one embodiment, Form N has a D[V,0.90]particle size between about 8 μm and about 200 μm. In one embodiment,the Form N has a D[V,0.90] particle size between about 8 μm and about100 μm. In one embodiment, the Form N has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the Form N has a D[4,3] particle size between about 5μm to about 200 μm. In one embodiment, the Form N has a D[4,3] particlesize between about 5 μm to about 150 μm. In one embodiment, the Form Nhas a D[4,3] particle size between about 5 μm and about 100 μm. In oneembodiment, the Form N has a D[4,3] particle size between about 5 μm andabout 75 μm. In one embodiment, the Form N has a D[4,3] particle sizebetween about 5 μm and about 50 μm. In one embodiment, the Form N has aD[4,3] particle size between about 5 μm and about 25 μm. In oneembodiment, the Form N has a D[4,3] particle size between about 10 μmand about 50 μm. In one embodiment, the Form N has a D[4,3] particlesize between about 10 μm and about 30 μm.

In one embodiment, the amorphous form has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 μm, or a D[4,3] particle size of about5 μm to about 200 μm.

In one embodiment, the amorphous form has a D[V,0.10] particle sizebetween about 0.5 μm and about 15 μm. In one embodiment, the amorphousform has a D[V,0.10] particle size between about 0.5 μm and about 10 μm.In one embodiment, the amorphous form has a D[V,0.10] particle sizebetween about 0.5 μm and about 5 μm.

In one embodiment, the amorphous form has a D[V,0.50] particle sizebetween about 2 μm and about 30 μm. In one embodiment, the amorphousform has a D[V,0.50] particle size between about 2 μm and about 25 μm.In one embodiment, the amorphous form has a D[V,0.50] particle sizebetween about 2 μm and about 20 μm. In one embodiment, the amorphousform has a D[V,0.50] particle size between about 2 μm and about 15 μm.

In one embodiment, the amorphous form has a D[V,0.90] particle sizebetween about 8 μm and about 600 μm. In one embodiment, the amorphousform has a D[V,0.90] particle size between about 8 μm and about 500 μm.In one embodiment, the amorphous form has a D[V,0.90] particle sizebetween about 8 μm and about 400 μm. In one embodiment, the amorphousform has a D[V,0.90] particle size between about 8 μm and about 300 μm.In one embodiment, the amorphous form has a D[V,0.90] particle sizebetween about 8 μm and about 200 μm. In one embodiment, the amorphousform has a D[V,0.90] particle size between about 8 μm and about 100 μm.In one embodiment, the amorphous form has a D[V,0.90] particle sizebetween about 8 μm and about 75 μm.

In one embodiment, the amorphous form has a D[4,3] particle size betweenabout 5 μm to about 200 μm. In one embodiment, the amorphous form has aD[4,3] particle size between about 5 μm to about 150 μm. In oneembodiment, the amorphous form has a D[4,3] particle size between about5 μm and about 100 μm. In one embodiment, the amorphous form has aD[4,3] particle size between about 5 μm and about 75 μm. In oneembodiment, the amorphous form has a D[4,3] particle size between about5 μm and about 50 μm. In one embodiment, the amorphous form has a D[4,3]particle size between about 5 μm and about 25 μm. In one embodiment, theamorphous form has a D[4,3] particle size between about 10 μm and about50 μm. In one embodiment, the amorphous form has a D[4,3] particle sizebetween about 10 μm and about 30 μm.

In one aspect, the present disclosure relates to a compositioncomprising a crystalline or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide has one or more of a D[V,0.10]particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particlesize between about 2 μm and about 30 μm, a D[V,0.90] particle sizebetween about 8 μm and about 600 μm, or a D[4,3] particle size of about5 μm to about 200 μm.

In one embodiment, the composition comprises a crystalline or amorphousform of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.10] particlesize between about 0.5 μm and about 15 μm. In one embodiment, thecomposition comprises a crystalline or amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.10] particlesize between about 0.5 μm and about 10 μm. In one embodiment, thecomposition comprises a crystalline or amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.10] particlesize between about 0.5 μm and about 5 μm.

In one embodiment, the composition comprises a crystalline or amorphousform of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.50] particlesize between about 2 μm and about 30 μm. In one embodiment, thecomposition comprises a crystalline or amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.50] particlesize between about 2 μm and about 25 μm. In one embodiment, thecomposition comprises a crystalline or amorphous form of a hydrobromidesalt of (S)(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.50] particlesize between about 2 μm and about 20 μm. In one embodiment, thecomposition comprises a crystalline or amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.50] particlesize between about 2 μm and about 15 μm.

In one embodiment, the composition comprises a crystalline or amorphousform of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.90] particlesize between about 8 μm and about 600 μm. In one embodiment, thecomposition comprises a crystalline or amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.90] particlesize between about 8 μm and about 500 μm. In one embodiment, thecomposition comprises a crystalline or amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.90] particlesize between about 8 μm and about 400 μm. In one embodiment, thecomposition comprises a crystalline or amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.90] particlesize between about 8 μm and about 300 μm. In one embodiment, thecomposition comprises a crystalline or amorphous form of a hydrobromidesalt of (S)(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.90] particlesize between about 8 μm and about 200 μm. In one embodiment, thecomposition comprises a crystalline or amorphous form of a hydrobromidesalt of (S)(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.90] particlesize between about 8 μm and about 100 In one embodiment, the compositioncomprises a crystalline or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[V,0.90] particlesize between about 8 μm and about 75 μm.

In one embodiment, the composition comprises a crystalline or amorphousform of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[4,3] particle sizebetween about 5 μm and about 200 In one embodiment, the compositioncomprises a crystalline or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[4,3] particle sizebetween about 5 μm and about 150 In one embodiment, the compositioncomprises a crystalline or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[4,3] particle sizebetween about 5 μm and about 100 In one embodiment, the compositioncomprises a crystalline or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[4,3] particle sizebetween about 5 μm and about 75 In one embodiment, the compositioncomprises a crystalline or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[4,3] particle sizebetween about 5 μm and about 50 In one embodiment, the compositioncomprises a crystalline or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[4,3] particle sizebetween about 10 μm and about 50 μm. In one embodiment, the compositioncomprises a crystalline or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[4,3] particle sizebetween about 10 μm and about 40 In one embodiment, the compositioncomprises a crystalline or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having a D[4,3] particle sizebetween about 10 μm and about 30 μm.

In one embodiment, the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having one or more of aD[V,0.10] particle size between about 0.5 μm and about 15 μm, aD[V,0.50] particle size between about 2 μm and about 30 μm, a D[V,0.90]particle size between about 8 μm and about 600 or a D[4,3] particle sizeof about 5 μm to about 200 μm is an amorphous form. In one embodiment,the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having one or more of aD[V,0.10] particle size between about 0.5 μm and about 15 μm, aD[V,0.50] particle size between about 2 μm and about 30 μm, a D[V,0.90]particle size between about 8 μm and about 600 or a D[4,3] particle sizeof about 5 μm to about 200 μm is a crystalline form. In one embodiment,the amorphous or crystalline hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having one or more of aD[V,0.10] particle size between about 0.5 μm and about 15 μm, aD[V,0.50] particle size between about 2 μm and about 30 μm, a D[V,0.90]particle size between about 8 μm and about 600 or a D[4,3] particle sizeof about 5 μm to about 200 μm is a compound of Formula (I)

In one embodiment, the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydroaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having one or more of aD[V,0.10] particle size between about 0.5 μm and about 15 μm, aD[V,0.50] particle size between about 2 μm and about 30 μm, a D[V,0.90]particle size between about 8 μm and about 600 μm, or a D[4,3] particlesize of about 5 μm to about 200 μm is a compound of Formula (II)

In one embodiment, the crystalline form is selected from the groupconsisting of Form A, Form B, Form C, Form D, Form E, Form F, Form F′,Form G, Form H, Form H′, Form J, Form K, Form L, Form M, and Form N. Inone embodiment, the crystalline form is Form A.

In some embodiments, the crystalline form is Form A which has one ormore particle parameters selected from the group consisting ofD[V,0.10], D[V,0.50], D[V,0.90], and D[4,3]. In other embodiments, thecrystalline form is Form A has two or more particle parameters selectedfrom the group consisting of D[V,0.10], D[V,0.50], D[V,0.90], andD[4,3].

Each of the embodiments described herein can be combined with any otherembodiment described herein not inconsistent with the embodiment withwhich it is combined.

In other embodiments, the crystalline form is Form A having a D[V,0.10]of from about 0.5 μm to about 15 μm; from about 0.5 μm to about 10 μm;from about 0.5 μm to about 5 μm; from about 1 μm to about 15 μm; fromabout 1 μm to about 10 μm; from about 1 μm to about 7.5 μm; from about 1μm to about 5 μm; from about 2 μm to about 10 μm; from about 2 μm toabout 7.5 μm; from about 2 μm to about 5 μm; from about 3 μm to about 10μm; from about 3 μm to about 7.5 μm; or from about 3 μm to about 5 μm.In other embodiments, the crystalline form is Form A having a D[V,0.10]of less than 15 μm; less than 12.5 μm; less than 10 μm; less than 9 μm;less than 8 μm; less than 7 μm; less than 6 μm; less than 5 μm; lessthan 4 μm; or less than 3 μm.

In other embodiments, the crystalline form is Form A having a D[V,0.50]of from about 2 μm to about 30 μm; 2 μm to about 20 μm; from about 2 μmto about 15 μm; from about 2 μm to about 10 μm; from about 5 μm to about30 μm; from about 5 μm to about 25 μm; from about 5 μm to about 20 μm;from about 5 μm to about 15 μm; from about 5 μm to about 10 μm; fromabout 7.5 μm to about 30 μm; from about 7.5 μm to about 25 μm; fromabout 7.5 μm to about 20 μm; from about 7.5 μm to about 15 μm; fromabout 7.5 μm to about 10 μm; from about 10 μm to about 30 μm; from about10 μm to about 25 μm; from about 10 μm to about 20 μm; from about 10 μmto about 15 μm; from about 12 μm to about 15 μm; from about 15 μm toabout 30 μm; from about 15 μm to about 25 μm; from about 15 μm to about20 μm; from about 20 μm to about 30 μm. In other embodiments, thecrystalline form is Form A having a D[V,0.50] of less than 30 μm; lessthan 25 μm; less than 20 μm; less than 15 μm; less than 12.5 μm; or lessthan 10 μm.

In other embodiments, the crystalline form is Form A having a D[V,0.90]of from about 8 μm to about 600 μm; from about 8 μm to about 575 μm;from about 8 μm to about 550 μm; from about 8 μm to about 525 μm; fromabout 8 μm to about 500 μm; from about 8 μm to about 475 μm; from about8 μm to about 450 μm; from about 8 μm to about 425 μm; from about 8 μmto about 400 μm; from about 8 μm to about 375 μm; from about 8 μm toabout 350 μm; from about 8 μm to about 325 μm; from about 8 μm to about300 μm; from about 8 μm to about 275 μm; from about 8 μm to about 250μm; from about 8 μm to about 225 μm; from about 8 μm to about 200 μm;from about 8 μm to about 175 μm; from about 8 μm to about 150 μm; fromabout 8 μm to about 175 μm; from about 8 μm to about 150 μm; from about8 μm to about 125 μm; from about 8 μm to about 100 μm; from about 8 μmto about 75 μm; from about 8 μm to about 50 μm; from about 8 μm to about40 μm; from about 8 μm to about 30 μm; from about 10 μm to about 600 μm;from about 10 μm to about 575 μm; from about 10 μm to about 550 μm; fromabout 10 μm to about 525 μm; from about 10 μm to about 500 μm; fromabout 10 μm to about 475 μm; from about 10 μm to about 450 μm; fromabout 10 μm to about 425 μm; from about 10 μm to about 400 μm; fromabout 10 μm to about 375 μm; from about 10 μm to about 350 μm; fromabout 10 μm to about 325 μm; from about 10 μm to about 300 μm; fromabout 10 μm to about 275 μm; from about 10 μm to about 250 μm; fromabout 10 μm to about 225 μm; from about 10 μm to about 200 μm; fromabout 10 μm to about 175 μm; from about 10 μm to about 150 μm; fromabout 10 μm to about 125 μm; from about 10 μm to about 100 μm; fromabout 10 μm to about 75 μm; from about 10 μm to about 60 μm; from about10 μm to about 50 μm; from about 25 μm to about 600 μm; from about 25 μmto about 575 μm; from about 25 μm to about 550 μm; from about 25 μm toabout 525 μm; from about 25 μm to about 500 μm; from about 25 μm toabout 475 μm; from about 25 μm to about 450 μm; from about 25 μm toabout 425 μm; from about 25 μm to about 400 μm; from about 25 μm toabout 375 μm; from about 25 μm to about 350 μm; from about 25 μm toabout 325 μm; from about 25 μm to about 300 μm; from about 25 μm toabout 275 μm; from about 25 μm to about 250 μm; from about 25 μm toabout 225 μm; from about 25 μm to about 200 μm; from about 25 μm toabout 175 μm; from about 25 μm to about 150 μm; from about 25 μm toabout 125 μm; from about 25 μm to about 100 μm; from about 25 μm toabout 75 μm; from about 25 μm to about 50 μm; from about 40 μm to about600 μm; from about 40 μm to about 575 μm; from about 40 μm to about 550μm; from about 40 μm to about 525 μm; from about 40 μm to about 500 μm;from about 40 μm to about 475 μm; from about 40 μm to about 450 μm; fromabout 40 μm to about 425 μm; from about 40 μm to about 400 μm; fromabout 40 μm to about 375 μm; from about 40 μm to about 350 μm; fromabout 40 μm to about 325 μm; from about 40 μm to about 300 μm; fromabout 40 μm to about 275 μm; from about 40 μm to about 250 μm; fromabout 40 μm to about 225 μm; from about 40 μm to about 200 μm; fromabout 40 μm to about 175 μm; from about 40 μm to about 150 μm; fromabout 40 μm to about 125 μm; from about 40 μm to about 100 μm; fromabout 40 μm to about 75 μm; from about 40 μm to about 50 μm; from about50 μm to about 600 μm; from about 50 μm to about 575 μm; from about 50μm to about 550 μm; from about 50 μm to about 525 μm; from about 50 μmto about 500 μm; from about 50 μm to about 475 μm; from about 50 μm toabout 450 μm; from about 50 μm to about 425 μm; from about 50 μm toabout 400 μm; from about 50 μm to about 375 μm; from about 50 μm toabout 350 μm; from about 50 μm to about 325 μm; from about 50 μm toabout 300 μm; from about 50 μm to about 275 μm; from about 50 μm toabout 250 μm; from about 50 μm to about 225 μm; from about 50 μm toabout 200 μm; from about 50 μm to about 175 μm; from about 50 μm toabout 150 μm; from about 50 μm to about 125 μm; from about 50 μm toabout 100 μm; from about 50 μm to about 75 μm; from about 75 μm to about600 μm; from about 75 μm to about 575 μm; from about 75 μm to about 550μm; from about 75 μm to about 525 μm; from about 75 μm to about 500 μm;from about 75 μm to about 475 μm; from about 75 μm to about 450 μm; fromabout 75 μm to about 425 μm; from about 75 μm to about 400 μm; fromabout 75 μm to about 375 μm; from about 75 μm to about 350 μm; fromabout 75 μm to about 325 μm; from about 75 μm to about 300 μm; fromabout 75 μm to about 275 μm; from about 75 μm to about 250 μm; fromabout 75 μm to about 225 μm; from about 75 μm to about 200 μm; fromabout 75 μm to about 175 μm; from about 75 μm to about 150 μm; fromabout 75 μm to about 125 μm; from about 75 μm to about 100 μm; fromabout 100 μm to about 600 μm; from about 100 μm to about 575 μm; fromabout 100 μm to about 550 μm; from about 100 μm to about 525 μm; fromabout 100 μm to about 500 μm; from about 100 μm to about 475 μm; fromabout 100 μm to about 450 μm; from about 100 μm to about 425 μm; fromabout 100 μm to about 400 μm; from about 100 μm to about 375 μm; fromabout 100 μm to about 350 μm; from about 100 μm to about 325 μm; fromabout 100 μm to about 300 μm; from about 100 μm to about 275 μm; fromabout 100 μm to about 250 μm; from about 100 μm to about 225 μm; fromabout 100 μm to about 200 μm; from about 100 μm to about 175 μm; fromabout 100 μm to about 150 μm; from about 100 μm to about 125 μm; fromabout 125 μm to about 600 μm; from about 125 μm to about 575 μm; fromabout 125 μm to about 550 μm; from about 125 μm to about 525 μm; fromabout 125 μm to about 500 μm; from about 125 μm to about 475 μm; fromabout 125 μm to about 450 μm; from about 125 μm to about 425 μm; fromabout 125 μm to about 400 μm; from about 125 μm to about 375 μm; fromabout 125 μm to about 350 μm; from about 125 μm to about 325 μm; fromabout 125 μm to about 300 μm; from about 125 μm to about 275 μm; fromabout 125 μm to about 250 μm; from about 125 μm to about 225 μm; fromabout 125 μm to about 200 μm; from about 125 μm to about 175 μm; fromabout 125 μm to about 150 μm; from about 125 μm to about 600 μm; fromabout 150 μm to about 575 μm; from about 150 μm to about 550 μm; fromabout 150 μm to about 525 μm; from about 150 μm to about 500 μm; fromabout 150 μm to about 475 μm; from about 150 μm to about 450 μm; fromabout 150 μm to about 425 μm; from about 150 μm to about 400 μm; fromabout 150 μm to about 375 μm; from about 150 μm to about 350 μm; fromabout 150 μm to about 325 μm; from about 150 μm to about 300 μm; fromabout 150 μm to about 275 μm; from about 150 μm to about 250 μm; fromabout 150 μm to about 225 μm; from about 150 μm to about 200 μm; fromabout 150 μm to about 175 μm; from about 175 μm to about 600 μm; fromabout 175 μm to about 575 μm; from about 175 μm to about 550 μm; fromabout 175 μm to about 525 μm; from about 175 μm to about 500 μm; fromabout 175 μm to about 475 μm; from about 175 μm to about 450 μm; fromabout 175 μm to about 425 μm; from about 175 μm to about 400 μm; fromabout 175 μm to about 375 μm; from about 175 μm to about 350 μm; fromabout 175 μm to about 325 μm; from about 175 μm to about 300 μm; fromabout 175 μm to about 275 μm; from about 175 μm to about 250 μm; fromabout 175 μm to about 225 μm; from about 175 μm to about 200 μm; fromabout 200 μm to about 600 μm; from about 200 μm to about 575 μm; fromabout 200 μm to about 550 μm; from about 200 μm to about 525 μm; fromabout 200 μm to about 500 μm; from about 200 μm to about 475 μm; fromabout 200 μm to about 450 μm; from about 200 μm to about 425 μm; fromabout 200 μm to about 400 μm; from about 200 μm to about 375 μm; fromabout 200 μm to about 350 μm; from about 200 μm to about 325 μm; fromabout 200 μm to about 300 μm; from about 200 μm to about 275 μm; fromabout 200 μm to about 250 μm; from about 200 μm to about 225 μm; fromabout 225 μm to about 600 μm; from about 225 μm to about 575 μm; fromabout 225 μm to about 550 μm; from about 225 μm to about 525 μm; fromabout 225 μm to about 500 μm; from about 225 μm to about 475 μm; fromabout 225 μm to about 450 μm; from about 225 μm to about 425 μm; fromabout 225 μm to about 400 μm; from about 225 μm to about 375 μm; fromabout 225 μm to about 350 μm; from about 225 μm to about 325 μm; fromabout 225 μm to about 300 μm; from about 225 μm to about 275 μm; fromabout 225 μm to about 250 μm; from about 250 μm to about 600 μm; fromabout 250 μm to about 575 μm; from about 250 μm to about 550 μm; fromabout 250 μm to about 525 μm; from about 250 μm to about 500 μm; fromabout 250 μm to about 475 μm; from about 250 μm to about 450 μm; fromabout 250 μm to about 425 μm; from about 250 μm to about 400 μm; fromabout 250 μm to about 375 μm; from about 250 μm to about 350 μm; fromabout 250 μm to about 325 μm; from about 250 μm to about 300 μm; fromabout 250 μm to about 275 μm; from about 275 μm to about 600 μm; fromabout 275 μm to about 575 μm; from about 275 μm to about 550 μm; fromabout 275 μm to about 525 μm; from about 275 μm to about 500 μm; fromabout 275 μm to about 475 μm; from about 275 μm to about 450 μm; fromabout 275 μm to about 425 μm; from about 275 μm to about 400 μm; fromabout 275 μm to about 375 μm; from about 275 μm to about 350 μm; fromabout 275 μm to about 325 μm; from about 275 μm to about 300 μm; fromabout 300 μm to about 600 μm; from about 300 μm to about 575 μm; fromabout 300 μm to about 550 μm; from about 300 μm to about 525 μm; fromabout 300 μm to about 500 μm; from about 300 μm to about 475 μm; fromabout 300 μm to about 450 μm; from about 300 μm to about 425 μm; fromabout 300 μm to about 400 μm; from about 300 μm to about 375 μm; fromabout 300 μm to about 350 μm; from about 300 μm to about 325 μm; fromabout 325 μm to about 600 μm; from about 325 μm to about 575 μm; fromabout 325 μm to about 550 μm; from about 325 μm to about 525 μm; fromabout 325 μm to about 500 μm; from about 325 μm to about 475 μm; fromabout 325 μm to about 450 μm; from about 325 μm to about 425 μm; fromabout 325 μm to about 400 μm; from about 325 μm to about 375 μm; fromabout 325 μm to about 350 μm; from about 350 μm to about 600 μm; fromabout 350 μm to about 575 μm; from about 350 μm to about 550 μm; fromabout 350 μm to about 525 μm; from about 350 μm to about 500 μm; fromabout 350 μm to about 475 μm; from about 350 μm to about 450 μm; fromabout 350 μm to about 425 μm; from about 350 μm to about 400 μm; fromabout 350 μm to about 375 μm; from about 375 μm to about 600 μm; fromabout 375 μm to about 575 μm; from about 375 μm to about 550 μm; fromabout 375 μm to about 525 μm; from about 375 μm to about 500 μm; fromabout 375 μm to about 475 μm; from about 375 μm to about 450 μm; fromabout 375 μm to about 425 μm; from about 375 μm to about 400 μm; fromabout 400 μm to about 600 μm; from about 400 μm to about 575 μm; fromabout 400 μm to about 550 μm; from about 400 μm to about 525 μm; fromabout 400 μm to about 500 μm; from about 400 μm to about 475 μm; fromabout 400 μm to about 450 μm; from about 400 μm to about 425 μm; fromabout 425 μm to about 600 μm; from about 425 μm to about 575 μm; fromabout 425 μm to about 550 μm; from about 425 μm to about 525 μm; fromabout 425 μm to about 500 μm; from about 425 μm to about 475 μm; fromabout 425 μm to about 450 μm; from about 450 μm to about 600 μm; fromabout 450 μm to about 575 μm; from about 450 μm to about 550 μm; fromabout 450 μm to about 525 μm; from about 450 μm to about 500 μm; fromabout 450 μm to about 475 μm; from about 475 μm to about 600 μm; fromabout 475 μm to about 575 μm; from about 475 μm to about 550 μm; fromabout 475 μm to about 525 μm; from about 450 μm to about 500 μm; fromabout 450 μm to about 475 μm; from about 500 μm to about 600 μm; fromabout 500 μm to about 575 μm; from about 500 μm to about 550 μm; fromabout 500 μm to about 525 μm; from about 550 μm to about 600 μm; fromabout 550 μm to about 575 μm; or from about 575 μm to about 600 μm. Inother embodiments, the crystalline form is Form A having a D[V,0.90] ofless than 600 μm, less than 575 μm, less than 550 μm, less than 525 μm,less than 500 μm, less than 475 μm, less than 450 μm, less than 425 μm,less than 400 μm, less than 375 μm, less than 350 μm, less than 325 μm,less than 300 μm, less than 275 μm, less than 250 μm, less than 225 μm,less than 200 μm, less than 175 μm; less than 150 μm; less than 125 μm;less than 100 μm; less than 75 μm; or less than 50 μm.

In other embodiments, the crystalline form is Form A having a D[4,3] offrom about 5 μm to about 200 μm; from about 5 μm to about 175 μm; fromabout 5 μm to about 150 μm; from about 5 μm to about 125 μm; from about5 μm to about 100 μm; from about 5 μm to about 75 μm; from about 5 μm toabout 50 μm; from about 5 μm to about 40 μm; from about 5 μm to about 25μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm;from about 10 μm to about 150 μm; from about 10 μm to about 125 μm; fromabout 10 μm to about 100 μm; from about 10 μm to about 75 μm; from aboutfrom about 10 μm to about 50 μm; from about 10 μm to about 40 μm; fromabout 10 μm to about 25 μm; from about 15 μm to about 200 μm; from about15 μm to about 175 μm; from about 15 μm to about 150 μm; from about 15μm to about 125 μm; from about 15 μm to about 100 μm; from about 15 μmto about 75 μm; from about 15 μm to about 50 μm; from about 15 μm toabout 40 μm; from about 15 μm to about 25 μm; from about 20 μm to about200 μm; from about 20 μm to about 175 μm; from about 20 μm to about 150μm; from about 20 μm to about 125 μm; from about 20 μm to about 100 μm;from about 20 μm to about 75 μm; from about 20 μm to about 50 μm; fromabout 25 μm to about 200 μm; from about 25 μm to about 175 μm; fromabout 25 μm to about 150 μm; from about 25 μm to about 125 μm; fromabout 25 μm to about 100 μm; from about 25 μm to about 75 μm; from about25 μm to about 50 μm; from about 25 μm to about 40 μm; from about 50 μmto about 200 μm; from about 50 μm to about 175 μm; from about 50 μm toabout 150 μm; from about 50 μm to about 125 μm; from about 50 μm toabout 100 μm; from about 50 μm to about 75 μm; from about 75 μm to about200 μm; from about 75 μm to about 175 μm; from about 75 μm to about 150μm; from about 75 μm to about 125 μm; from about 75 μm to about 100 μm;from about 100 μm to about 200 μm; from about 100 μm to about 175 μm;from about 100 μm to about 150 μm; from about 100 μm to about 125 μm;from about 125 μm to about 200 μm; from about 125 μm to about 175 μm;from about 125 μm to about 150 μm; from about 150 μm to about 200 μm;from about 150 μm to about 175 μm; or from about 175 μm to about 200 μm.In other embodiments, the crystalline form is Form A having a D[4,3] ofless than 200 μm; less than 175 μm; less than 150 μm; less than 125 μm;less than 100 μm; less than 75 μm; 50 μm; less than 40 μm; less than 30μm; or less than 25 μm.

A hydrobromide salt form of Compound 1 can be prepared based on thesynthetic schemes set forth in U.S. Pat. No. 7,795,447, which isincorporated herein by reference in its entirety. In some embodiments,the particular crystalline or amorphous form of hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having the desired particlesize is the product of the synthesis. In other embodiments, theparticular crystalline or amorphous hydrobromide salt(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having the desired particlesize is prepared using further processing steps following synthesis.Examples of such processing steps include, but are not limited to,recrystallization and milling, such as jet milling.

In some embodiments, the particle size is determined by laserdiffraction (e.g., Sympatec Helos and QicPic) at 3.0 bar dispersionpressure.

Particle sizes for the crystalline materials may be assessed using laserdiffraction methods. Laser diffraction is recognized by standards andguidance agencies including ISO and ASTM and is widely used to determineparticle size distributions. In conducting the assessment, the sample ispassed through a laser beam which results in laser light scattered at arange of angles. Detectors placed at fixed angles measure the intensityof light scattered at that position. A mathematical model (Mie orFraunhoffer Theory) is then applied to generate a particle sizedistribution.

The particle size was analyzed using the laser diffraction (or smallangle light scattering) technique by dispersing the dry sample powderwith compressed air. Specifically, the particle size distribution wasanalyzed using the Sympatec HELOS RODOS system equipped with a Vibri drypowder feeder. The powder sample was dispersed with a dispersionpressure of 0.5 bar. In some instances, an Aspiros micro-dosing devicewas used, and the powder sample was dispersed with a dispersion pressureof 0.2 bar. A suitable lens was selected to cover the particle sizerange of each sample.

In particle size determinations, the median value is defined as thevalue where half of the population resides above this point, and halfresides below this point. For particle size distributions the median iscalled the D50. The D50 is the size in microns that splits thedistribution with half above and half below this diameter. Theexpression Dv50 or D[v,0.5] is sometimes used for the median of a volumedistribution.

The mode is the peak of a frequency distribution. A particledistribution may include more than one mode, e.g., where the particlesexist as primary particles and agglomerations.

The span is sometimes used as a measurement of distribution width and isdefined as the ratio of (D[v,0.9]−D[v,0.1])/D[v,0.5] or (D90−D10)/D50.

The distribution width may also be characterized by citing one, two orpreferably three values, typically some combination of the D10, D50, andD90. The D50, the median, has been defined above as the diameter wherehalf of the population lies below this value. Similarly, 90 percent ofthe distribution lies below the D90, and 10 percent of the populationlies below the D10.

The term D[4,3] refers to the volume mean or mass moment mean. Laserdiffraction results are reported on a volume basis and the volume meancan be used to define the central point of the distribution. The D[4,3]value is sensitive to the presence of large particles in thedistribution.

IV. Pharmaceutical Compositions

Forms A-N and amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) may beadministered to subjects via the oral, parenteral (such as subcutaneous,intravenous, intramuscular, intrasternal and infusion techniques),rectal, intranasal, topical or transdermal (e.g., through the use of apatch) routes. In one embodiment, crystalline Form A of the compound ofFormula (I) may be administered to subjects via the oral, parenteral(such as subcutaneous, intravenous, intramuscular, intrasternal andinfusion techniques), rectal, intranasal, topical or transdermal (e.g.,through the use of a patch) routes.

In one embodiment, the pharmaceutical composition comprises crystallineForm A of the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I). In oneembodiment, the pharmaceutical composition is an oral tablet comprisingone or more of Forms A-N and amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) and apharmaceutically acceptable carrier. In one embodiment, the tabletcomprises about 25 mg to about 400 mg of one or more of Forms A-N andamorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II). In oneembodiment, the tablet comprises about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg,about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg,about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg,about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg,about 195 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg,about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mgof the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide as one or more of Forms A-N oramorphous. In one embodiment, the tablet comprises about 50 mg of thehydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methy-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of one or more of Forms A-Nand amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II). In oneembodiment, the tablet comprises about 100 mg of the hydrobromide saltof(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide one or more of Forms A-N andamorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II). In oneembodiment, the tablet comprises about 150 mg of one or more of FormsA-N and amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II).

For oral administration, known carriers can be included in thepharmaceutical composition. For example, microcrystalline cellulose,sodium citrate, calcium carbonate, dicalcium phosphate and glycine maybe employed along with various disintegrants such as starch (preferablycorn, potato or tapioca starch), methylcellulose, alginic acid andcertain complex silicates, together with granulation binders such aspolyvinylpyrrolidone, sucrose, gelatin and acacia, can be included in atablet. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers ingelatin capsules. Preferred materials in this connection include lactoseor milk sugar as well as high molecular weight polyethylene glycols.When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient may be combined with varioussweetening or flavoring agents, coloring matter or dyes, and, if sodesired, emulsifying and/or suspending agents as well, together withsuch diluents as water, ethanol, propylene glycol, glycerin and variouslike combinations thereof.

For parenteral administration, solutions containing Compound 1 can beprepared in either sesame or peanut oil, in aqueous propylene glycol, orin sterile water or saline. The aqueous solutions should be suitablybuffered (preferably pH greater than 8) if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theseaqueous solutions are suitable for intravenous injection purposes. Theoily solutions are suitable for intraarticular, intramuscular andsubcutaneous injection purposes. The preparation of all these solutionsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well known to those skilled in the art.

V. Methods of Treatment

Forms A-N and amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) may beused to modulate or inhibit the Notch signaling pathway in organisms,including humans. Notch signaling is frequently elevated in a variety ofhuman tumors (including, but not limited to breast, prostate, pancreasand T-cell acute lymphoblastic leukemia).

Accordingly, Forms A-N and amorphous form of the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) may beadministered to treat a subject with tumors or cancer, including, butnot limited to desmoid tumors, multiple myeloma, adenoid cysticcarcinoma, and T-cell acute lymphoblastic leukemia. In one embodiment,crystalline Form A of the compound of Formula (I) may be administered totreat a subject with tumors or cancer, including, but not limited todesmoid tumors, multiple myeloma, adenoid cystic carcinoma, and T-cellacute lymphoblastic leukemia. In one embodiment, crystalline Form A ofthe compound of Formula (I) and a pharmaceutically acceptable carriermay be administered to treat a subject with tumors or cancer, including,but not limited to desmoid tumors, multiple myeloma, adenoid cysticcarcinoma, and T-cell acute lymphoblastic leukemia. In one embodiment,Forms A-N and amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) may beadministered to treat tumors, including desmoid tumors. In oneembodiment, Forms A-N and amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) may beadministered to treat a cancer having a mutation in a Notch pathwaygene. In one embodiment, Forms A-N and amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) may beadministered to treat multiple myeloma. Forms A-N and amorphous form ofa hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) may beadministered to treat adenoid cystic carcinoma. Forms A-N and amorphousform of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) may beadministered to treat T-cell acute lymphoblastic leukemia.

In one embodiment, one or more of Forms A-N and amorphous form of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) isadministered in doses ranging from about 0.1 mg to about 1000 mg perday. In one embodiment, a subject is administered about 50 mg to about500 mg of one or more of Forms A-N and amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) daily.In another embodiment, a subject is administered about 100 mg to about400 mg of one or more of Forms A-N and amorphous form of a hydrobromidesalt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) daily.In another embodiment, a subject is administered about 100 mg, about 125mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375mg, or about 400 mg daily of one or more of Forms A-N and amorphous formof a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II). Thetotal daily dose can be provided as single or divided doses (i.e., 1, 2,3, or 4 doses per day). In one embodiment, the total daily dose isprovided as two doses. For example, a 300 mg or 200 mg total daily dosecan be administered to a subject as two separate 150 mg or 100 mg doses,respectively. In one embodiment, three tablets comprising 50 mg of oneor more of Forms A-N and amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II) twicedaily or 200 mg daily dose can be administered to a subject as twotablets comprising 50 mg of one or more of Forms A-N and amorphousCompound 1 of Formula (I) or (II) twice daily.

In one aspect, the present disclosure relates to a use of one or more ofForms A-N or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II)discussed above for treating tumors or cancer. In one embodiment, thepresent disclosure relates to a use of crystalline Form A of ahydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) for treatingtumors or cancer. In one embodiment, the present disclosure relates tothe pharmaceutical composition discussed above for treating tumors orcancer. In one embodiment, the use is for treating desmoid tumors. Inone embodiment, the use is for treating cancer selected from the groupconsisting of multiple myeloma, a cancer having a mutation in a Notchpathway gene, adenoid cystic carcinoma, and T-cell acute lymphoblasticleukemia.

In one aspect, the present disclosure relates to one or more of FormsA-N or amorphous form of a hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) or (II)discussed above for use in a method for treatment of tumors or cancer.In one embodiment, the present disclosure relates to crystalline Form Aof the hydrobromide salt of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I) for use in amethod for treatment of tumors or cancer. In one embodiment, the presentdisclosure relates to the pharmaceutical composition discussed above foruse in a method for treatment of tumors or cancer. In one embodiment,the use is for treating desmoid tumors. In one embodiment, the use isfor treating cancer selected from the group consisting of multiplemyeloma, a cancer having a mutation in a Notch pathway gene, adenoidcystic carcinoma, and T-cell acute lymphoblastic leukemia.

EXAMPLES A. Abbreviations and Acronyms

NMR Nuclear Magnetic Resonance Spectroscopy XRPD X-ray PowderDiffraction PLM Polarized Light Microscopy TGA ThermogravimetricAnalysis DSC Differential Scanning Calorimetry TG-IR ThermogravimetricInfrared analysis FE Fast Evaporation SE Slow Evaporation S/ASSolvent/Anti-solvent CP Crash Precipitation LLD Liquid Liquid DiffusionLVD Liquid Vapor Diffusion SC Slow Cooling FC Fast Cooling CC CrashCooling LIMS Laboratory Information Management System B/EBirefringence/Extinction RT Room/ambient Temperature RH RelativeHumidity VO Vacuum Oven ACN Acetonitrile CHCl3 Chloroform DCMDichloromethane DCE Dichloroethane DEE Diethyl ether DMAN,N-dimethylacetamide DMF N,N-dimethylformamide DMSO Dimethyl sulfoxideEtOAc Ethyl acetate EtOH Ethanol H2O Water HFIPA HexafluoroisopropanolIPA Isopropanol IpOAc Isopropyl acetate MCH Methyl cyclohexane MeOHMethanol MEK Methyl ethyl ketone MIBK Methyl-iso-butyl ketone MTBEMethyl-tert-butyl ether NMP N-methyl-2-pyrrolidone PG Propylene glycolTFE Trifluroethanol THF Tetrahydrofuran

B. Experimental Methods Example 1: Approximate Kinetic Solubility

Weighed samples of material were treated with aliquots of specifiedsolvents at ambient temperature. Samples were typically sonicatedbetween additions to facilitate dissolution. Complete dissolution wasobserved through visual inspection. Solubility was calculated based onthe total amount of solvent added to achieve complete dissolution andmay be greater than the value reported due to incremental solventaddition and the inherent kinetics of dissolution. If dissolution wasnot observed, values are reported as “less than”. If dissolution wasobserved upon the first addition of solvent, values are reported as“greater than”. Table 1 shows kinetic solubility of dihydrobromide saltof(s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamide.

TABLE 1 Solubility Estimate Solvent (a) (mg/mL) Acetone <1 Acetone/CHCl₃50/50 <1 ACN <1 ACN/CHCl₃ 50/50 <1 ACN/EtOAc 50/50 <1 Chloroform <1 DCE<1 Dioxane ′<1 DMA 8 DMF 18 DMF/ACN 30/70 <1 DMF/ACN 60/40 3 DMF/EtOAc50/50 <1 DMF/IPA 60/40 5 DMF/MIBK 80/20 4 DMSO 63 DMSO/MTBE 10/90 <1Ethylene Glycol 7 EtOAc <1 EtOH <1 EtOH/DCM 50/50 <1 Heptane/CHCl₃ 30/70<1 MEK/DMF (b) 40/60 2 MeOH 19 MeOH/Acetone 50/50 6 MeOH/CHCl₃ 50/50 13MeOH/EtOAc 50/50 2 MeOH/MTBE 80/20 7 NMP 10 NMP/Acetone 85/15 7NMP/EtOAc 57/43 1 PG (b) 2 TFE (anhydrous) 10 TFE/MEK 70/30 2 THF (b) <1THF/CHCl₃ 50/50 1 THF/CHCl₃ 25/75 <1 THF/CHCl₃ (b) 85/15 <1 Toluene <1Water 7 Acetone/H₂O 30/70 14 ACN/H₂O 50/50 36 Dioxane/H₂O (b) 50/50 19DMF/H₂O 50/50 24 DMF/H₂O 30/70 17 EtOH/H₂O 40/60 10 IPA/H₂O 50/50 15MeOH/H₂O 20/80 9 THF/H₂O 80/20 24 THF/H₂O 90/10 4 (a) Solubilityestimated using solvent addition method via visual assessment ofsamples. Values are rounded to nearest whole number and reported as ″<″if dissolution was not observed. (b) non-cGMP samples.

Example 2: Stable Form and Hydrate Screen

Method a: Trituration Experiments

Samples of dihydrobromide salt of(s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamidewere triturated at ambient or set temperature in specified solventsystems. After approximately 24 hours, solids were isolated bycentrifugation using eppendorf centrifuge tubes equipped with a 0.45 μmnylon filter. The agitation was then continued in fresh solvents for atotal of ˜1 and 3 weeks, after which the solids were isolated asdescribed above, observed under polarized light and analyzed by)(RFD.

Method b: Equilibrium Solubility Testing

Equilibrium solubility of solids isolated were determinedgravimetrically as follows. Measured aliquots of mother liquor solutionsfrom the 3-week slurries were place in pre-weighed aluminum TGA pans.Subsequently, solvents were evaporated under ambient conditions or usingvacuum. Remaining solids were weighed.

Table 2 shows results of stable form and hydrate screen.

TABLE 2 Solubility XRPD (mg/mL) Solvent system, conditions (a)Observations Results (b) DMA (anhydrous) 1 week Unknown morphology; B/EForm A — DMA (anhydrous) 3 weeks Unknown morphology; B/E Form A 27DMF/ACN (65/35) 1 week Unknown morphology; B/E Form A — DMF/ACN (65/35)3 weeks Unknown morphology; B/E Form A 10 DMF/IPA (60/40) 1 week Unknownmorphology; B/E Form A — DMF/IPA (60/40) 3 weeks Unknown morphology; B/EForm A 13 DMF/MIBK (85/15) 1 week Unknown morphology; B/E Form A —DMF/MIBK (85/15) 3 weeks Unknown morphology; B/E Form A 19 DMSO/MTBE(anhydrous) (30/70) Unknown morphology; B/E Form A — 1 day (c) MEK/DMF(20/80) 1 week Unknown morphology; B/E Form A — MEK/DMF (20/80) 3 weeksUnknown morphology; B/E Form A 17 MeOH (anhydrous) 2-8° C. (d) Unknownmorphology, small Form A — 1 week particles; B/E MeOH (anhydrous) 2-8°C. (d) Unknown morphology + some Form A 13 3 weeks needle-like; B/EMeOH/Acetone (anhydrous) (50/50) Unknown morphology, small Form A — 1week particles; B/E MeOH/Acetone (anhydrous) (50/50) Unknown morphology,Form A  7 3 weeks extremely small; B/E MeOH/CHCl3 (anhydrous) (40/60)Unknown morphology; B/E Form A — 1 week MeOH/CHCl3 (anhydrous) (40/60)Unknown morphology + some Form A 22 3 weeks needle-like; B/E MeOH/EtOAc(anhydrous) (70/30) Unknown morphology, small Form A — 1 week particles;B/E MeOH/EtOAc (anhydrous) (70/30) Unknown morphology; B/E Form A  6 3weeks MeOH/MTBE (anhydrous) (80/20) Unknown morphology, small Form A — 1week particles; B/E MeOH/MTBE (anhydrous) (80/20) Unknown morphology +some Form A 12 3 weeks needle-like; B/E NMP (anhydrous) 1 week Unknownmorphology; B/E Form A — NMP (anhydrous) 3 weeks Unknown morphology,very Form A 50 small; B/E NMP/Acetone (anhydrous) (85/15) Unknownmorphology, very Form A — 1 week small particles; B/E NMP/Acetone(anhydrous) (85/15) Unknown morphology; B/E Form A 36 3 weeks NMP/EtOAc(anhydrous) (80/20) Unknown morphology + small Form A — 1 week needles;B/E NMP/EtOAc (anhydrous) (80/20) Unknown morphology; B/E Form A 25 3weeks PG 1 week Unknown morphology; B/E Form A — PG 3 weeks Unknownmorphology, Form A  8 extremely small; B/E TFE (anhydrous) 3 weeksUnknown morphology; B/E Form A — TFE/MEK (anhydrous) (85/15) Unknownmorphology; B/E Form A — 1 week TFE/MEK (anhydrous) (85/15) Unknownmorphology, Form A 3 weeks extremely small; B/E H₂O 1 week Unknownmorphology; B/E Form A — H₂O 3 weeks Very small needles; B/E Form A 14Acetone/H₂O (50/50) 1 week Unknown morphology, very Form A — smallparticles; B/E Acetone/H₂O (50/50) 3 weeks Unknown morphology, Form A 43extremely small; B/E Dioxane/H₂O (70/30) 1 week Unknown morphology,small Form A — particles; B/E Dioxane/H₂O (70/30) 3 weeks Unknownmorphology + some Form A 24 needles; B/E IPA/H₂O (60/40) 1 week Unknownmorphology, very Form A — small particles; B/E IPA/H₂O (60/40) 3 weeksUnknown morphology, Form A 26 extremely small; B/E EtOH/H₂O (60/40) 1week Unknown morphology; B/E Form A — EtOH/H₂O (60/40) 3 weeks Extremelysmall needles; B/E Form A 36 EtOH/H₂O (60/40) 2-8° C. (d) 1 week Unknownmorphology, small Form A — particles; B/E EtOH/H₂O (60/40) 2-8° C. (c) 3weeks Unknown morphology, Form A 33 extremely small; B/E MeOH/H₂O(20/80) 1 week Unknown morphology, small Form A — particles; B/EMeOH/H₂O (20/80) 3 weeks Extremely small needles; B/E Form A 17 THF/H₂O(85/15) 1 week Unknown morphology; B/E Form A — THF/H₂O (85/15) 3 weeksUnknown morphology, Form A 25 extremely small; B/E (a) Experiments wereconducted for a total of ~1 week and ~3 weeks, both with solventreplacement after ~1 day of slurrying. Solvent ratios (v/v) and durationof experiments are approximate. Experiments were performed at ambientconditions unless otherwise specified, (b) Solubility determinedgravimetrically. (c) After the initial solvent exchange, there was aninsufficient amount of solids to use for further slurry. (d) Conductedin a cold room. (e) non-cGMP samples.

Example 3: Polymorph Screen

Dihydrobromide salt of(s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamide,unless noted otherwise, was used as the starting material. Materialsproduced in the study were utilized for selected experiments.

Starting materials were subjected to crystallization techniques, whichare summarized below. Solids were typically isolated by vacuumfiltration, observed under polarized light and analyzed by XRPD.

Method a: Grinding Experiments

Solids were combined with small amounts of solvent and transferred to anagate milling container. An agate ball was added and the containerattached to a Retsch mill. The sample was typically milled for eitherone cycle of twenty minutes at 30 Hz, or repacked and the cycle repeatedfor an additional 20 minutes.

Method b: Slurry Experiments

Solids were suspended in specified solvents. The suspensions were thenagitated at ambient or set temperature. After a given amount of timesolids were isolated.

Method c: Solvent/Anti-Solvent Precipitation

Solutions of starting material were prepared at ambient or elevatedtemperature and filtered using 0.2 μm nylon filters. They were thenmixed with appropriate anti-solvents at elevated temperature. If nosolids were observed, the samples were either cooled to ambient orsub-ambient temperatures or other crystallization techniques applied.

Method d: Crash Precipitation

Solutions of starting material were prepared at elevated temperature inspecified solvents and hot-filtered through 0.2 μm nylon filters intoappropriate anti-solvents pre-cooled on a dry ice/acetone or water/icebath. If solids precipitated, they were immediately isolated by vacuumfiltration while still cold. If the solution remained clear, the samplewas either kept at sub-ambient temperatures or further crystallizationtechniques were applied.

Method e: Cooling Experiments

Solutions of starting material were prepared in specified solvents atelevated temperature using a hot plate for heating. These were typicallyhot-filtered through a 0.2 μm nylon filter into warm receiving vials.The vials were either quickly transferred into a sub-ambient temperaturebath (typically dry ice/acetone) for crash cooling (CC), removed fromthe hot place for fast cooling (FC) or the heat was turned off to allowfor slow cooling (SC). If solids precipitated, they were isolated coldby vacuum filtration. If the solution remained clear, the sample waseither kept at sub-ambient temperatures or further crystallizationtechniques were applied.

Method f: Evaporation Experiments

Solutions of starting material were allowed to partially evaporate orevaporate to dryness at ambient or elevated temperature from open vialsfor fast evaporation (FE) or from vials covered with aluminum foil withpin holes for slow evaporation (SE). Prior to evaporation, solutionswere filtered at ambient or elevated temperature using 0.2 μm nylonfilters.

Method g: Liquid-Vapor Diffusion Experiments

Solutions of starting material were prepared at ambient temperature andfiltered through 0.2 μm nylon filters into receiving vials. The openvials were then placed into secondary containers with appropriateanti-solvents. The containers were sealed and left undisturbed atambient conditions.

Method h: Vapor Stress Experiments

Solids of starting material were transferred to vials which were placeduncapped into secondary containers with appropriate anti-solvents. Thesecondary containers were sealed and left undisturbed at ambient orsub-ambient conditions.

Method i: Low Relative Humidity Stress Experiments

Solids of starting material were transferred to a vial which was placed,uncapped, into a RH jar containing P205. It was kept at ambienttemperature for a specified duration.

Method j: Drying Experiments

Solids of starting material were dried at ambient or under reducedpressure at a set temperature for a specified duration.

Table 3 summarizes the polymorph screen results for dihydrobromide saltof(s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamide.

TABLE 3 Solvent system Conditions (a) Observations XRPD Results ACNSlurry, 45° C., 2 days Unknown morphology; Form A B/E DCE Slurry, 45°C., 2 days Unknown morphology; Form A B/E DMA/DMSO (89/11) FC attemptfrom 44° C. to RT Insufficient amount of — (clear). Transferred tofreezer, solids 13 days. Sonicated, FE followed by SE and then by FE atRT (small needles present in solution). Transferred back to freezer, 13days. DMF FC attempt from 44° C. to RT Unknown morphology; Form A(clear). Transferred to freezer, B/E 13 days. Sonicated, FE followed bySE and then by FE at RT (solids). Transferred back to freezer, 13 days.DMF/MIBK (80/20) SC attempt, 45° C. to RT over Insufficient amount of —2 days. Transferred to freezer, solids 8 days. Sonicated, FE followed bySE and then by FE at RT (small needles present in solution). Transferredback to freezer, 13 days. DMSO/MTBE Mother liquor; FE Unknownmorphology; Form A (30/70) B/E EtOAc Slurry, 45° C., 2 days Unknownmorphology; Form A B/E H₂O Slurry, RT, 4 days Unknown morphology; Form AB/E HFIPA SE Unknown morphology; Form F B/E SE Unknown morphology + FormJ small needles; B/E MeOH (anhydrous) Mother liquor; FE B/E particleswithin a Form B, 2-8° C. (b) transparent matrix disordered MeOH/AcetoneMother liquor; FE Opaque particles; no Form C (anhydrous) (50/50) B/EMeOH/Acetone FE, 40° C. Unknown morphology + Form B, (50/50) smallneedles; B/E disordered FE, RT Unknown morphology + Form B, translucentparticles; disordered B/E MeOH/ACN S/AS attempt, AS addition at Unknownmorphology; Form A, 45° C. (clear); volume B/E disordered reduction byFE at 45° C. (gel- like solids). Added AS at 45° C., transferred tofreezer, ~1 month. MeOH/CHCl3 Mother liquor; FE Unknown morphology;Disordered, (anhydrous) (40/60) B/E with peaks of Form A MeOH/EtOAcMother liquor; FE Glass — (anhydrous) (70/30) MeOH/MTBE CP attempt 45°C./sub-RT, ice Unknown morphology + Form A bath (viscous solids). Icebath, small needles; B/E 2 hours, then kept at RT, 20 days. — Fromviscous solids of 6094- Unknown morphology + Form B, 34-04. glassyparticles; B/E disordered Added heptane to viscous solids, FE at RT.NMP/EtOAc (70/30) SC attempt, 45° C. to RT over No solids — 2 days.Transferred to freezer, 8 days. Sonicated, then FE at RT. TFE/MEK Motherliquor; FE Unknown morphology + Form A (anhydrous) (85/15) glass; B/ETFE/MEK CP attempt 45° C./sub-RT (ice Unknown morphology; Form A(anhydrous) bath). Transferred to freezer, B/E 7 days. Isolated solidswhile cold. Acetone/H₂O (50/50) Mother liquor; FE Glass + some B/E FormB, particles disordered DMSO/H₂O (4/96) CC attempt from 44° C. toInsufficient — sub-RT (ice/H20 bath, clear). amount of solids Kept inrefrigerator, 13 days (clear). Sonicated, FE at RT (some solids).Transferred back to refrigerator, ~5 months. Dioxane/H₂O (70/30) Motherliquor; FE Unknown morphology + Form A, needles; B/E possibly with X-rayamorphous content Dioxane/H₂O (50/50) FE, 45° C. Unknown morphology +Form B, small, dendritic disordered needles; B/E Lyophilization, −35° C.— X-ray amorphous Lyophilization, −50° C. — X-ray amorphous IPA/H₂O(60/40) Mother liquor; FE Rosettes within a Form A, glassy matrix +possibly with unknown morphology; X-ray B/E amorphous content IPA/H₂O(50/50) FE, 45° C. Unknown morphology; Form B, B/E disordered EtOH/H₂O(60/40) Mother liquor; FE Needles + unknown Disordered, morphology; B/Ewith peaks of Form A EtOH/H₂O (60/40) FE, 45° C. Unknown morphology;Form D + peaks B/E EtOH/H₂O (60/40) Mother liquor; FE Unknownmorphology + Form B, 2-8° C. (b) needles; B/E disordered MeOH/H₂O(20/80) Mother liquor; FE Unknown morphology + Form B, glass; B/Edisordered THF/H₂O (85/15) Mother liquor; FE Unknown morphology; Form B,some B/E disordered (a) Solvent ratios (v/v), temperature, and durationof experiments are approximate. Refrigerator and cold room temperature:2-8° C.; freezer temperature: between −10° C. and −25° C. (b) The motherliquor was obtained from the slurry at 2-8° C. The evaporation was atambient temperature. (c) non-cGMP samples.

Table 4 summarizes the polymorph screen results for dihydrobromide saltof(s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamide starting from X-ray amorphousmaterial.

TABLE 4 Solvent system Conditions (b) Observations XRPD ResultsCHCl3/Heptane Stirring, CHCl3, RT, 3 Unknown morphology, Form E, 43/57(anhydrous) days (viscous solids). extremely small; B/E crystalline withAdded heptane at RT disorder (small, fine solids); slurry, 1 day. EtOHSlurry, RT, 3 days Unknown morphology, Form A very small; B/EMEK/Heptane Stirring, MEK, RT, 3 days Unknown morphology + Form G, 62/38(anhydrous) (viscous solids). Added some opaque particles; disorderedheptane at RT (small, fine B/E solids + some viscous); slurry, 1 day.Toluene Vapor stress, RT, 6 days Opaque particles + a X-ray fewparticles with B/E amorphous DCM Vapor stress, freezer, 6 Unknownmorphology; Form H, days B/E disordered, Solvent present. possiblycontains Form A MeOH/Acetone LVD, RT Unknown morphology + Form A(anhydrous) needles; B/E Dioxane Grinding; 1 cycle, 30 Hz, Unknownmorphology + Form B, (anhydrous) 20 minutes some translucent disordered,particles; B/E possibly contains Form G IpOAc Grinding; 1 cycle, 30 Hz,Unknown morphology + Form A, 20 minutes small needles; B/E disorderedDCE FE, 30° C., then cooled to Unknown morphology; Disordered RT andtransferred to No suitable crystals for freezer structure determinationAcetone/MeOH/ S/AS, added AS at 30° C. Very thin needles; B/E Form A MCH14/17/69 Kept at 30° C., 3-4 hours, then cooled to RT. CHCl3 Saturatedsolution, kept at Insufficient — RT, 1 day. Transferred to amount ofsolids freezer, ~5 months. (a) All samples generated from LIMS 386797are non-cGMP. (b) Solvent ratios (v/v), temperature, and duration ofexperiments are approximate. Refrigerator and cold room temperature:2-8° C.; freezer temperature: between −10° C. and −25° C.

Example 4: Preparation of X-ray Amorphous Material

A solution of starting material was prepared in dioxane/water (50/50) atambient temperature and filtered into a round bottom flask. The flaskwas submerged into a dry ice/acetone bath to freeze the solution. Oncefrozen, it was attached to a lyophilizer at approximately −50° C. fortwo days.

Example 5: Preparation of Selected Materials

Table 5 summarizes the preparation conditions for selected materials.

TABLE 5 Targeted Material Solvent System Conditions (a) ObservationsXRPD Results Form B MeOH FE, RT Unknown Form B, morphology; B/Edisordered FE, RT. Unknown Form B, Stored solids in morphology; B/Edisordered freezer. SE, RT. — Analyzed wet. Stored solids in Form Dfreezer. From 6094-34-02. Unknown Form A Vapor stress, RT. morphology;B/E Stored solids in freezer. Prepared saturated No solids — solution at45° C., then SC to RT. Transferred to freezer. MeOH/Acetone FE, 45° C.Unknown Form D 50/50 Stored solids in morphology, B/E freezer. particlesencapsulated in solvent MeOH/Acetone Prepared saturated Small needles;Form A solution in MeOH at B/E 45° C.; added acetone at elevatedtemperature. SC to RT (cloudy). MeOH/HFIPA SE, RT. — Analyzed wet. 60/40Stored solids in Form M freezer. Acetone/H2O SE, then FE, RT. Glassy —50/50 SC, 50° C. to RT No solids — Transferred to freezer. MeOH/MTBELVD, RT. Unknown Form B, Air-dried solids. morphology + disorderedglassy; B/E Form C MeOH/Acetone FE, 45° C. Unknown Form C (anhydrous)morphology; B/E + 50/50 some opaque particles MeOH/Acetone FE, 45° C. —Form C + small (anhydrous) Solids stored in peaks 50/50 freezer. — From6141-67-02. VO, — Form C + small RT, 1 day. peaks MeOH/Acetone Slurry,RT, 1 day; Unknown Form C + small (anhydrous) centrifuged solids andmorphology, small peaks 50/50 FE of mother liquor. particles; someStored solids in B/E freezer. Form D EtOH/H2O FE, 45° C. Unknown FormD + peaks, morphology + may also contain small needles; B/E Form A 60/40FE, 45° C. — Analyzed wet. Stored in freezer Disordered, contains Form DSC, 45° C. to RT, then Glass — FE, RT. Slurry, RT Unknown Form Amorphology, small particles; B/E MeOH/H2O Slurry, RT Unknown Form A35/65 morphology; B/E Form E CHCl3/Heptane Slurry, RT, 7 days; UnknownX-ray (b) (anhydrous) added heptane, morphology + amorphous 43/57transferred to freezer, glassy; some B/E 10 days. Added heptane, then SEat ambient. Stored solids in freezer. CHCl3/Heptane Slurry, CHCl3, RT, 5Unknown Form E, (anhydrous) days (viscous). Added morphology; B/Eimproved (33/67) heptane. Slurry, RT, 7 crystallinity days. Form H DCMSlurry, RT, 7 days; Unknown Form K, (b) added DCM, morphology; B/Edisordered transferred to freezer, 10 days, then SE at ambient. Storedsolids in freezer. Vapor stress, freezer, Unknown Similar to Form 13days. morphology; B/E H, disordered Form G MEK/Heptane SC from 45° C.;Viscous — (b) (anhydrous) transferred to freezer, 58/42 14 days, then SEat ambient. MEK/Heptane Slurry, MEK, RT, 5 Unknown Form A (anhydrous)days (viscous). Added morphology + (43/57) heptane. Slurry, RT, 7needles; B/E days. Form F HFIPA SE Unknown Similar to Form (b)morphology; B/E F Form J HFIPA SE. Unknown Form L Stored solids inmorphology; B/E freezer. Vapor stress Solids dissolved — From6141-53-02. Unknown Form F + peaks; SE, RT. Stored solids morphology;B/E poorly in freezer. crystalline Grinding; 2 cycles, 30 Unknown FormA + peaks, Hz, 20 minutes morphology, small decreased particles; B/Ecrystallinity (a) Solvent ratios (v/v), temperature, and duration ofexperiments are approximate. Refrigerator and cold room temperature:2-8° C.; freezer temperature: between −10° C. and −25° C. (b) X-rayamorphous material was used as starting material. Material is non-cGMP.(c) non-cGMP samples.

Table 6 summarizes the drying conditions for selected materials.

TABLE 6 Starting Material Conditions (a) XRPD Results Similar to VO, 45°C., 1 day Consistent with Form F Form F Form F VO, 77° C., 1 dayConsistent with Form F; poorly crystalline Form D VO, 75° C., 1 dayConsistent with Form D Dried on P205, RT, Consistent with Form D, 17days selected peaks RH at prep.: 3% slightly shifted RH at run: 43% FormM Air drying, 1 day Similar to Form F Form E 120° C., 8 hoursDisordered, similar to Form B (a) Temperature, RH, and duration ofexperiments are approximate.

Example 6: Interconversion Experiments

Starting materials, except for Form A, were dried in a vacuum oven at45° C. for approximately 1 day. Saturated solutions of Form A inspecified solvent systems were prepared and seeds of the dried materialsand of Form A were added. The samples were agitated in sealed vials atambient temperature for approximately one week.

Table 7 summarizes results for interconversion experiments.

TABLE 7 Starting XRPD Material (a) Conditions (b) Results Seeds of FormA, Form D, MeOH Slurry, RT, 1 week Form A Form B, Form E, Form F,MEK/DMF 50/50 Slurry, Form A Form G, Form J RT, 1 week Seeds of Form A,Form D, EtOH/H2O 60/40 Slurry, Form A Form B, Form C, Form E, RT, 1 weekForm F, Form G, Form J (a) All materials excluding Form A were driedunder vacuum at 45° C. for ~1 day prior to the experiments. (b)Temperature and duration of experiments are approximate.

Example 7: Single Crystals Growth Experiments

Samples of Form A were treated using the following crystallizationtechniques. In attempts to induce crystallization, seeds of Form A wereadded in selected experiments.

Method a: Evaporation/Volume Reduction Experiments

Solutions of starting material were allowed to partially evaporate orevaporate to dryness at ambient or elevated temperature from open vialsfor fast evaporation (FE) or from vials capped loosely or covered withaluminum foil with pin holes for slow evaporation (SE). Prior toevaporation, solutions were filtered at ambient or elevated temperatureusing a 0.2 μm nylon filter.

Method b: Liquid-Vapor and Liquid-Liquid Diffusion Experiments

Solutions of starting material were prepared in specified solvents atambient temperature and typically filtered using a 0.2 μm nylon filter.For liquid vapor diffusion (LVD), vials with filtered solutions wereplaced in secondary containers with appropriate anti-solvents and leftundisturbed at ambient or sub-ambient temperature. For liquid-liquiddiffusion (LLD), solutions of tested material were carefully brought incontact with specified solvents and left undisturbed at ambient orsub-ambient temperature.

Method c: Cooling Experiments

Solutions of starting material were prepared at elevated temperatureusing a hot plate for heating. The solutions were then hot filteredusing a 0.2 μm nylon filter and left on the heating source and slowlycooled to a set temperature (SC). After a specified duration, they werefurther cooled to a sub-ambient temperature.

Table 8 summarizes single crystals growth results for Form A

TABLE 8 XRPD Solvent system Conditions (a) Observations Results DMF/DEELLD; kept in refrigerator, 6 No suitable crystals — weeks DMF/EtOAc LVDNo suitable crystals; Form A Unknown morphology; B/E DMF/IPA LVD, after15 days transferred No solids — to freezer, ~5 months. DMF/MEK LVD, 5days No suitable crystals; Form A Unknown morphology + small needles;B/E DMF/THF LVD, after 5 days, transferred No solids — to freezer, ~5months. MeOH/Acetone SE, 45° C., with seeding No suitable crystals; —(64/36) Unknown morphology, B/E MeOH/Acetone SE No suitable crystals;Form B, (50/50) Small, needle-like disordered particles; B/E MeOH/CHCl3SE Unknown morphology; Form B, (50/50) B/E disordered MeOH/ LLD Nosolids — Cyclohexane MeOH/DEE LLD; kept in refrigerator, 6 — — weeksMeOH/Heptane LLD — — MeOH/Heptane LLD, sub-ambient (freezer) No solids —MeOH/MTBE SE No suitable crystals; Form B, (80/20) Unknown morphology;disordered B/E NMP SC attempt, 45° C. to 30° C.; No solids — seeded withForm A; 30° C., 11 days. Transferred to freezer, 16 days. FE fromelevated temperature Needles + small particles, Form N, (40° C. to 30°C.), then cooled unknown morphology; may contain to RT and transferredto B/E Form C freezer. PG SC, 45° C. to 30° C.; seeded No solids — withForm A; 30° C., 11 days, then transferred to freezer, 16 days. (a)Solvent ratios (v/v), temperature, and duration of experiments areapproximate. Refrigerator and cold room temperature: 2-8° C.; freezertemperature: between −10° C. and −25° C. (b) non-cGMP samples.

Example 8: X-Ray Powder Diffraction (XRPD)

Method a: Transmission Geometry

XRPD patterns were collected with a PANalytical X'Pert PRO MPDdiffractometer using an incident beam of Cu radiation produced using anOptix long, fine-focus source. An elliptically graded multilayer mirrorwas used to focus Cu Kα X-rays through the specimen and onto thedetector. Prior to the analysis, a silicon specimen (NIST SRM 640d or640e) was analyzed to verify the observed position of the Si 111 peak isconsistent with the NIST-certified position. A specimen of the samplewas sandwiched between 3-μm-thick films and analyzed in transmissiongeometry. A beam-stop, short antiscatter extension, and an antiscatterknife edge were used to minimize the background generated by air. Sollerslits for the incident and diffracted beams were used to minimizebroadening from axial divergence. Diffraction patterns were collectedusing a scanning position-sensitive detector (X'Celerator) located 240mm from the specimen and Data Collector software v. 2.2b.

Method b. Reflection Geometry

XRPD patterns were collected with a PANalytical X'Pert PRO MPDdiffractometer using an incident beam of Cu Kα radiation produced usinga long, fine-focus source and a nickel filter. The diffractometer wasconfigured using the symmetric Bragg-Brentano geometry. Prior to theanalysis, a silicon specimen (NIST SRM 640d or 640e) was analyzed toverify the observed position of the Si 111 peak is consistent with theNIST-certified position. A specimen of the sample was prepared as a/thin, circular layer centered on a silicon zero-background substrate.Antiscatter slits (SS) were used to minimize the background generated byair. Soller slits for the incident and diffracted beams were used tominimize broadening from axial divergence. Diffraction patterns werecollected using a scanning position-sensitive detector (X'Celerator)located 240 mm from the sample and Data Collector software v. 2.2b.

Example 9: Thermogravimetric Analysis (TGA)

TGA analyses were performed using a TA Instruments 2050 or a Discoverythermogravimetric analyzer. Temperature calibration was performed usingnickel and Alumel™. Each sample was placed in an aluminum or platinumpan and inserted into the TG furnace. The furnace was heated under anitrogen purge. The method code on the thermogram is an abbreviation forthe start and end temperature as well as the heating rate; e.g.,25-350-10 means “from 25° C. to 350° C., at 10° C./min”.

Example 10: Differential Scanning Calorimetry (DSC)

DSC was performed using a TA Instruments Q2000 differential scanningcalorimeter. Temperature calibration was performed using NIST-traceableindium metal. The sample was placed into an aluminum DSC pan (TOC),covered with a lid, and the weight was accurately recorded. A weighedaluminum pan configured as the sample pan was placed on the referenceside of the cell. The method code on the thermogram is an abbreviationfor the start and end temperature as well as the heating rate; e.g.,−30-250-10 means “from ˜30° C. to 250° C., at 10° C./min”.

Example 11: Thermogravimetric-Infrared Spectroscopy (TG-IR)

Thermogravimetric infrared (TG-IR) analysis was performed on a TAInstruments thermogravimetric (TG) analyzer model 2050 interfaced to aMagna-IR 560® Fourier transform infrared (FT-IR) spectrophotometer(Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, apotassium bromide (KBr) beamsplitter, and a mercury cadmium telluride(MCT-A) detector. The FT-IR wavelength verification was performed usingpolystyrene, and the TG calibration standards were nickel and Alumel™.The sample was placed in a platinum sample pan, and the pan was insertedinto the TG furnace. The TG instrument was started first, immediatelyfollowed by the FT-IR instrument. The TG instrument was operated under aflow of helium at 90 and 10 cc/min, for the purge and balance,respectively. The furnace was heated under helium at a rate of 20°C./minute to a final temperature of 250° C. IR spectra were collectedapproximately every 32 seconds for approximately 13 minutes. Each IRspectrum represents 16 co-added scans collected at a spectral resolutionof 4 cm⁻¹. Volatiles were identified from a search of the HighResolution Nicolet Vapor Phase spectral library. Searches from thislibrary are considered non-cGMP.

Example 12: Polarized Light Microscopy (PLM)

Light microscopy was performed using a Leica DM LP microscope equippedwith a SPOT Insight™ color digital camera. Typically, each sample wasplaced on a glass slide, a cover glass was placed over the sample, and adrop of mineral oil was added to cover the sample by capillarity. Eachsample was observed using a 0.8-10.0×objective with crossed polarizersand a first order red compensator.

Example 14: Computational Methods (Indexing)

Successful indexing of an XRPD pattern indicates that the sample iscomposed primarily of a single crystalline phase. Agreement betweenallowed peak positions and observed peaks indicates a consistent unitcell determination. Indexing was performed using X'Pert High Score Plus2.2a (2.2.1) and TRIADS™. No attempts at molecular packing wereperformed to confirm the tentative indexing solution within the scope ofthis work.

1-144.
 145. A pharmaceutical composition comprising solid form of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I)

wherein the solid form has a D[V,0.90] particle size of about 100 μm.146. The pharmaceutical composition of claim 145, wherein the(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide has a D[V,0.10] particle sizeof about 0.5 μm.
 147. The pharmaceutical composition of claim 145,wherein the composition comprises about 50 mg(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide.
 148. The pharmaceuticalcomposition of claim 145, wherein the composition comprises about 50 mg(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide and provides a Tmax of morethan about 1 hour.
 149. The pharmaceutical composition of claim 148,wherein the composition comprises about 50 mg(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide and provides an in vivo areaunder the plasma curve (AUC) of less than 700 ng h/ml.
 150. Thepharmaceutical composition of claim 146, wherein the compositioncomprises about 50 mg(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide.
 151. The pharmaceuticalcomposition of claim 146, wherein the composition comprises about 50 mg(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide and provides a Tmax of morethan about 1 hour.
 152. The pharmaceutical composition of claim 151,wherein the composition comprises about 50 mg(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide and provides a an in vivo areaunder the plasma curve (AUC_(inf)) of less than 700 ng h/ml.
 153. Apharmaceutical composition of(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino) propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I)

the solid form having a D[V,0.10] particle size between about 0.5 μm andabout 15 μm, a D[V,0.50] particle size between about 2 μm and about 30μm, a D[V,0.90] particle size between about 8 μm and about 600 μm, or aD[4,3] particle size of about 5 μm to about 200 μm.
 154. Thepharmaceutical composition of claim 153, having two or more of: aD[V,0.10] particle size between about 0.5 μm and about 15 μm, aD[V,0.50] particle size between about 2 μm and about 30 μm, a D[V,0.90]particle size between about 8 μm and about 600 μm, and a D[4,3] particlesize of about 5 μm to about 200 μm.
 155. The pharmaceutical compositionof claim 154, wherein the composition comprises about 50 mg(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide.
 156. The pharmaceuticalcomposition of claim 153, wherein the composition comprises about 50 mg(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide and provides a Tmax of morethan about 1 hour.
 157. The pharmaceutical composition of claim 156,wherein the composition comprises about 50 mg(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide and provides a an in vivo areaunder the plasma curve (AUC_(inf)) of less than 700 ng h/ml.